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Lorazepam: Drug information

Lorazepam: Drug information
(For additional information see "Lorazepam: Patient drug information" and see "Lorazepam: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Risks from concomitant use with opioids (injection, oral):

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for 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.

Abuse, misuse, and addiction (injection, oral):

The use of benzodiazepines, including lorazepam, 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 lorazepam and throughout treatment, assess each patient's risk for abuse, misuse, and addiction.

Dependence and withdrawal reactions:

Injection: The continued use of benzodiazepines for several days to weeks may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Although lorazepam injection is indicated only for intermittent use, if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of lorazepam injection may precipitate acute withdrawal reactions, which can be life-threatening. For patients using lorazepam injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue lorazepam injection.

Oral: The continued use of benzodiazepines, including lorazepam, 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 lorazepam 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 lorazepam or reduce the dosage.

Brand Names: US
  • Ativan;
  • LORazepam Intensol;
  • Loreev XR
Brand Names: Canada
  • APO-LORazepam;
  • Ativan;
  • DOM-LORazepam [DSC];
  • PMS-LORazepam;
  • PRO-LORazepam;
  • TEVA-LORazepam
Pharmacologic Category
  • Anticonvulsant, Benzodiazepine;
  • Benzodiazepine
Dosing: Adult

Note: Reduce dose or avoid use in patients receiving opioids or with significant chronic disease (eg, respiratory compromise). Generally, avoid use in patients with, or at risk for, substance use disorders, except for acute or emergency situations (eg, acute agitation, status epilepticus).

Akathisia, antipsychotic-induced

Akathisia, antipsychotic-induced (alternative agent) (off-label use): Oral (immediate release): Initial: 0.5 to 1 mg twice daily; may increase dose based on response and tolerability up to 6 mg/day, in divided doses (Adler 1985; Bartels 1987; Lavonas 2021; Stroup 2021).

Anxiety

Anxiety:

Anxiety and agitation, acute/severe (monotherapy or adjunctive therapy): IM, IV, Oral (immediate release): 0.5 to 2 mg every 4 to 6 hours as needed up to 10 mg/day; adjust dose based on response and tolerability. In severely agitated inpatients, some experts recommend doses up to 4 mg and repeat IM or IV doses as frequently as 10 to 30 minutes; may give alone or in combination with an antipsychotic (Moore 2019).

Anxiety disorders (adjunctive therapy or monotherapy) (alternative agent): Note: Generally used short-term for symptom relief until preferred therapy (eg, serotonin reuptake inhibitor) is effective (eg, 4 to 6 weeks followed by tapering). Long-term low-dose therapy may be considered in individuals without a history of substance use, misuse of medications, or depression, when preferred treatments are ineffective or poorly tolerated (Craske 2021; Katzman 2014; WFSBP [Bandelow 2008]). Use with caution in patients with comorbid posttraumatic stress disorder (PTSD); benzodiazepines may worsen PTSD symptoms (VA/DoD 2017).

Immediate release: Oral: Initial: 0.5 to 1 mg 2 to 3 times daily; although most patients will experience relief with this dose, may increase daily dose gradually based on response and tolerability in increments of 1 mg every 2 to 3 days up to 6 mg/day in 2 to 4 divided doses; some patients may require doses up to 10 mg/day for optimal response. Some experts recommend a lower initial dose of 0.5 to 1 mg once to twice daily (Craske 2021; manufacturer's labeling).

Extended release 24-hour capsules: Oral: Initial: Determine stable daily dose using IR tablets in 3 divided doses. Maintenance: May convert to extended release at the total daily dose of immediate release; administer once daily in the morning. Note: For dosage adjustments, discontinue extended release and switch to immediate release.

Advanced cancer and/or palliative care: IM, IV, Oral (immediate release): 0.25 to 2 mg every 3 to 6 hours as needed (Irwin 2022; Roy-Byrne 2021). Note: The injectable solution may be administered rectally or subcutaneously, and the tablet and oral solution may be administered sublingually at the same doses when other routes are unavailable (Caillé 1983; Graves 1987; Greenblatt 1982; Harman 2020; Howard 2014; von Gunten 2019).

Performance- or phobia-related anxiety (monotherapy or adjunctive therapy): Note: Provide a test dose, at the same dose to be used for treatment, in advance of the stimulus to ensure tolerability (Stein 2019).

Oral (immediate release): 0.5 to 2 mg once 30 to 60 minutes before the stimulus (Stein 2019; Swinson 2019).

Procedural anxiety (premedication):

Oral (immediate release), Sublingual (off-label use): 0.5 to 2 mg once 30 to 90 minutes before procedure; if needed due to incomplete response, may repeat the dose (usually at 50% of the initial dose) after 30 to 60 minutes (Chang 2015; Choy 2019; Male 1984; Shih 2020).

IV: 1 to 4 mg or 0.02 to 0.04 mg/kg (maximum single dose: 4 mg) once 5 to 20 minutes before procedure; if needed based on incomplete response and/or duration of procedure, may repeat the dose (usually at 50% of the initial dose) after ≥5 minutes (Choy 2019; manufacturer's labeling). Note: In obese patients, nonweight-based dosing is preferred (Choy 2019).

Catatonia

Catatonia (off-label use):

Diagnosis: Note: Partial, temporary relief of signs following administration is consistent with the diagnosis; a negative response does not rule out catatonia (Coffey 2021a).

IV (preferred): 1 to 2 mg once; if no response in 5 to 10 minutes, repeat dose once (Coffey 2021a; Fink 2009; Rosebush 2010).

IM, Oral (immediate release), Sublingual: 2 mg once; may administer up to 2 additional doses at 3-hour intervals if needed (Coffey 2021a; Rosebush 2010).

Treatment: Note: For patients with malignant catatonia, electroconvulsive therapy should begin immediately (WFSBP [Hasan 2012]).

IM, IV, Oral (immediate release): Initial: 1 to 2 mg 3 times daily; IV preferred for initial dosing with switch to oral as patient improves. May increase dose based on response and tolerability in increments of 3 mg every 1 to 2 days to a usual dose of 6 to 21 mg/day. Doses up to 30 mg/day have been reported (Coffey 2021b; Daniels 2009; Fink 2009). For patients at risk of cardiorespiratory compromise or oversedation, some experts recommend initiating with 0.5 mg 3 times daily (Coffey 2021b; WFSBP [Hasan 2012]).

Duration of treatment: Remission is usually achieved in 4 to 10 days; maintenance therapy at the effective dose is usually continued for 3 to 6 months to maintain recovery, although longer courses may be needed (Coffey 2021b).

Chemotherapy-induced nausea and vomiting, prevention and treatment

Chemotherapy-induced nausea and vomiting, prevention and treatment (adjunctive therapy) (off-label use):

Anticipatory or breakthrough nausea/vomiting, as an adjunct to conventional antiemetics: Oral (immediate release), IV, Sublingual: 0.5 to 1 mg every 6 hours as needed; doses up to 2 mg have been described (Lohr 2008).

Intoxication

Intoxication: Cocaine, methamphetamine, and other sympathomimetics (off-label use): Based on limited data: IV: 2 to 4 mg every 3 to 10 minutes as needed for agitation, sedation, seizures, hypertension, and tachycardia until desired symptom control achieved. Large cumulative doses may be required for some patients; monitor for respiratory depression and hypotension (Arnold 2019; Boyer 2019b; Nelson 2022; Wodarz 2017). Note: Initiating treatment at 1 mg may be adequate in patients who are only mildly or moderately intoxicated, but doses should be repeated or increased as needed. Consider IM administration if IV access is not possible; however, effects will be delayed (Arnold 2019).

Mechanically ventilated patients in the ICU, sedation

Mechanically ventilated patients in the ICU, sedation (alternative agent) (off-label use): Note: Used as part of a multimodal strategy. In general, nonbenzodiazepine sedation is preferred due to risk of prolonged sedation and delirium with continuous benzodiazepine use. Titrate to light level of sedation (eg, Richmond Agitation-Sedation Scale 0 to −2) or clinical effect (eg, ventilator dyssynchrony). Intermittent as-needed therapy is preferred to avoid drug accumulation and prolonged sedation associated with continuous infusions (SCCM [Devlin 2018]). For obese patients, fixed dosing is preferred; alternatively, some use IBW for weight-based dosing (Tietze 2022). Continuous infusions are not recommended for use in most ICU patients due to propylene glycol (PG) accumulation and subsequent complications (osmol gap metabolic acidosis, kidney failure); monitor PG accumulation with osmol gap; nonbenzodiazepine or midazolam continuous infusions are generally preferred (Arroliga 2004; Barnes 2006; Yahwak 2008).

Intermittent (preferred):

Non–weight-based dosing: IV: Initial dose: 1 to 4 mg; Maintenance: 1 to 4 mg every 2 to 6 hours as needed (Carson 2006; Tietze 2022).

Weight-based dosing: IV: Initial dose: 0.02 to 0.04 mg/kg (maximum single dose: 4 mg); Maintenance: 0.02 to 0.06 mg/kg every 2 to 6 hours as needed (maximum single dose: 4 mg) (Carson 2006; Cernaianu 1996; Rozendaal 2009; SCCM [Barr 2013]; Tietze 2022).

Continuous infusion: IV: 0.5 to 10 mg/hour or 0.01 to 0.1 mg/kg/hour continuous infusion (maximum dose: 10 mg/hour) (Rozendaal 2009; SCCM [Barr 2013]; Tietze 2022).

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome (adjunctive therapy) (off-label use): Note: For management of muscle rigidity or anxiety in patients with severe symptoms at presentation (hyperthermia, evidence of rhabdomyolysis) and for those not responding to initial withdrawal of medication and supportive care:

IM, IV: 0.5 to 2 mg every 4 to 6 hours until symptom resolution. Use higher doses (eg, 1 to 2 mg) for management of muscle rigidity (Wijdicks 2019).

Seizures

Seizures: Note: If IV access is not available, IM lorazepam is not recommended due to erratic absorption and a slow time to peak drug levels. May consider sublingual or subcutaneous lorazepam or IM midazolam (Drappatz 2019; Harman 2020; Leppik 2015).

Acute active seizures (non-status epilepticus) (off-label use): IV: 4 mg given at a maximum rate of 2 mg/minute; may repeat at 3 to 5 minutes if seizures continue (Drislane 2020; McKee 2015; O’Connor 2020; Schachter 2020).

Status epilepticus: IV: 4 mg given at a maximum rate of 2 mg/minute; may repeat at 3 to 5 minutes if seizures continue; a nonbenzodiazepine antiseizure agent should follow to prevent seizure recurrence, even if seizures have ceased (Drislane 2020; manufacturer's labeling).

Serotonin syndrome

Serotonin syndrome (serotonin toxicity) (off-label use): IV: 2 to 4 mg IV every 8 to 10 minutes based upon patient response (Boyer 2020).

Substance withdrawal

Substance withdrawal:

Alcohol withdrawal syndrome (alternative agent) (off-label use): Note: Symptom-triggered regimens preferred over fixed-dose regimens. Dosage and frequency may vary based on institution-specific protocols. Although longer-acting benzodiazepines are preferred in general, shorter-acting benzodiazepines, including lorazepam, may be preferable in patients with impaired liver function. Some experts recommend avoiding IM administration due to variable absorption (Hoffman 2019; WFSBP [Soyka 2017]).

Symptom-triggered regimen: Oral (immediate release), IV: 2 to 4 mg as needed; dose and frequency determined by withdrawal symptom severity using a validated severity-assessment scale such as the Clinical Institute Withdrawal Assessment for Alcohol, revised scale (CIWA-Ar) (Hoffman 2019; WFSBP [Soyka 2017]).

Fixed-dose regimen: Oral (immediate release), IV: 1 to 4 mg every 4 to 6 hours for 1 day, then gradually taper dose over 3 to 4 days; additional doses may be considered based on withdrawal symptoms and validated assessment scale scores (eg, CIWA-Ar) (ASAM 2020; Malcolm 2002; Myrick 2009; WFSBP [Soyka 2017]).

Opioid withdrawal (autonomic instability and agitation) (adjunctive therapy) (alternative agent) (off-label use): Based on limited data: IV: 1 to 2 mg every 10 minutes until hemodynamically stable and adequate sedation (Hanna 2018; Stolbach 2019; Wightman 2018).

Vertigo, acute episodes, treatment

Vertigo, acute episodes, treatment (alternative agent) (off-label use): IM, IV, Oral (immediate release): 0.5 to 2 mg every 4 to 12 hours as needed for 24 to 48 hours (Basura 2020; Furman 2021; Hain 2003; Swartz 2005).

Discontinuation of therapy: Unless safety concerns require a more rapid withdrawal, gradually taper to detect reemerging symptoms and minimize rebound and withdrawal symptoms (Lader 2011; VA/DoD 2015). Low or moderate dose, no concerns for benzodiazepine use disorder: Taper total daily dose by 20% to 25% every 1 to 2 weeks based on response and tolerability (taper increments will be limited by available dosage forms) (Craske 2021; VA/DoD 2015). Extended or high-dose therapy, or suspected benzodiazepine use disorder: Taper total daily dose by 25% to 50% every 1 to 2 weeks based on response, tolerability, and individual patient factors (taper increments will be limited by available dosage forms) (Park 2021; VA/DoD 2015). The optimal duration will vary; up to 6 months may be necessary for some patients on higher doses (VA/DoD 2015). Taper more rapidly in the beginning, and slow the reduction rate as the taper progresses because earlier stages of withdrawal are easier to tolerate (Lader 2011; VA/DoD 2015). For benzodiazepines with half-lives significantly <24 hours, including lorazepam, consider substituting an equivalent dose of a long-acting benzodiazepine to allow for a more gradual reduction in drug serum concentrations (Lader 2011; VA/DoD 2015).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Altered kidney function: Mild to severe impairment:

Oral: No dosage adjustment necessary (Morrison 1984; Verbeeck 1976).

Parenteral: No dosage adjustment necessary for acute doses (Morrison 1984; Verbeeck 1976); use repeated doses with caution; may increase the risk of propylene glycol toxicity. Monitor osmol gap closely as a surrogate marker for propylene glycol accumulation, especially if using for prolonged periods of time or at high doses (Arroliga 2004; Barnes 2006; Yahwak 2008).

Hemodialysis, intermittent (thrice weekly): Not significantly dialyzed (Morrison 1984; Verbeeck 1976): Oral, Parenteral: No supplemental dose or dosage adjustment necessary; use repeated parenteral doses with caution; monitor osmol gap closely as a surrogate marker for propylene glycol accumulation, especially if using for prolonged periods of time or at high doses (expert opinion).

Peritoneal dialysis: Unlikely to be dialyzed (highly protein bound): Oral, Parenteral: No dosage adjustment necessary (expert opinion); use repeated parenteral doses with caution; monitor osmol gap closely as a surrogate marker for propylene glycol accumulation, especially if using for prolonged periods of time or at high doses (expert opinion).

CRRT: Not significantly dialyzed (Swart 2004): Oral, Parenteral: No dosage adjustment necessary (expert opinion); use repeated intravenous doses with caution; monitor osmol gap closely as a surrogate marker for propylene glycol accumulation, especially if using for prolonged periods of time or at high doses (expert opinion).

PIRRT (eg, sustained, low-efficiency diafiltration): Unlikely to be dialyzed (highly protein bound): Oral, Parenteral: No dosage adjustment necessary (expert opinion); use repeated parenteral doses with caution; monitor osmol gap closely as a surrogate marker for propylene glycol accumulation, especially if using for prolonged periods of time or at high doses (expert opinion).

Dosing: Hepatic Impairment: Adult

Oral:

Mild to moderate impairment: No dosage adjustment necessary.

Severe impairment and/or encephalopathy: Use with caution; may require lower doses.

Parenteral:

Mild to moderate impairment: No dosage adjustment necessary; use with caution.

Severe impairment or failure: Although manufacturer labeling suggests use is not recommended, clearance does not appear to be influenced by hepatic disease; use with caution (Kraus 1978; Peppers 1996).

Dosing: Pediatric

(For additional information see "Lorazepam: Pediatric drug information")

Chemotherapy-induced nausea and vomiting, anticipatory: Limited data available: Infants, Children, and Adolescents: Oral: 0.04 to 0.08 mg/kg/dose; maximum dose: 2 mg/dose; administer a dose the night before chemotherapy and again the next day prior to chemotherapy administration (Dupuis 2014).

Chemotherapy-associated nausea and vomiting, breakthrough: Limited data available: Children and Adolescents: IV: 0.025 to 0.05 mg/kg/dose every 6 hours as needed; maximum dose: 2 mg/dose (Dupuis 2003).

Anxiety, acute:

Infants and Children <12 years: Limited data available: Oral, IV: Usual: 0.05 mg/kg/dose (maximum dose: 2 mg/dose) every 4 to 8 hours; range: 0.02 to 0.1 mg/kg/dose (Gal 2007).

Children ≥12 years and Adolescents: Oral: 0.25 to 2 mg/dose 2 or 3 times daily; maximum dose: 2 mg/dose (Kliegman 2011).

Sedation (preprocedure): Limited data available: Children and Adolescents: Oral: Usual: 0.05 mg/kg; range reported in literature: 0.02 to 0.09 mg/kg (Burtles 1983; Henry 1991; Mundeleer 1980; Peters 1982). Note: In adults, the maximum dose is 4 mg/dose.

Status epilepticus: Limited data available:

IV: Infants, Children, and Adolescents: 0.1 mg/kg slow IV; may repeat dose once in 5 to 10 minutes; maximum dose: 4 mg/dose (AES [Glauser 2016]; NCS [Brophy 2012]).

Intranasal: Note: Lorazepam is not the preferred agent for intranasal administration, guidelines recommend midazolam as the preferred agent (AES [Glauser 2016]).

Infants, Children, and Adolescents: 0.1 mg/kg/dose; maximum dose: 5 mg/dose (Ahmad 2006; Arya 2011; Kliegman 2020).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Oral: Children ≥12 years and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling; however, some clinicians recommend no dosage adjustments are necessary (Aronoff 2007).

IV: No dosage adjustment necessary for acute doses; use repeated doses with caution; may increase the risk of propylene glycol toxicity. Monitor closely if using for prolonged periods of time or at high doses. In adults, the osmolar gap has been shown to be a surrogate marker for propylene glycol accumulation (Arroliga 2004; Barnes 2006; Yahwak 2008).

Dosing: Hepatic Impairment: Pediatric

Children ≥12 years and Adolescents: No dosage adjustment necessary. For severe hepatic disease, use with caution; benzodiazepines may worsen hepatic encephalopathy.

Dosing: Older Adult

Refer to adult dosing. Dose selection should generally be on the low end of the dosage range (initial dose of immediate release not to exceed 2 mg).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule ER 24 Hour Sprinkle, Oral:

Loreev XR: 1 mg [contains corn starch, tartrazine (fd&c yellow #5)]

Loreev XR: 2 mg [contains corn starch, fd&c yellow #10 (quinoline yellow)]

Loreev XR: 3 mg [contains brilliant blue fcf (fd&c blue #1), corn starch, fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Concentrate, Oral:

LORazepam Intensol: 2 mg/mL (30 mL) [alcohol free, dye free, sugar free; contains polyethylene glycol, propylene glycol; unflavored flavor]

Generic: 2 mg/mL (30 mL)

Solution, Injection:

Ativan: 2 mg/mL (1 mL, 10 mL); 4 mg/mL (1 mL, 10 mL) [contains benzyl alcohol, polyethylene glycol, propylene glycol]

Generic: 2 mg/mL (1 mL, 10 mL); 4 mg/mL (1 mL, 10 mL)

Tablet, Oral:

Ativan: 0.5 mg

Ativan: 1 mg, 2 mg [scored]

Generic: 0.5 mg, 1 mg, 2 mg

Generic Equivalent Available: US

May be product dependent

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection:

Generic: 2 mg/mL (1 mL); 4 mg/mL (1 mL)

Tablet, Oral:

Ativan: 0.5 mg, 1 mg, 2 mg

Generic: 0.5 mg, 1 mg, 2 mg

Tablet Sublingual, Sublingual:

Ativan: 0.5 mg [contains fd&c blue #1 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Ativan: 1 mg

Ativan: 2 mg [contains fd&c blue #2 aluminum lake]

Generic: 0.5 mg, 1 mg, 2 mg

Controlled Substance

C-IV

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Ativan: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017794s044lbl.pdf

Administration: Adult

IM: Should be administered (undiluted) deep into the muscle mass.

IV injection: Dilute prior to use (according to the manufacturer). Do not exceed 2 mg/minute or 0.05 mg/kg over 2 to 5 minutes. Monitor IV site during administration. Avoid intra-arterial administration. Avoid extravasation.

Oral:

ER capsule: Administer with or without food. Do not crush or chew. Swallow whole or open and sprinkle the entire contents of capsule over a tablespoon of applesauce, then drink water after consuming the applesauce (without chewing). Consume entire contents of capsule within 2 hours of opening capsule.

Oral concentrate: Use only the provided calibrated dropper to withdraw the prescribed dose. Mix the dose with liquid (eg, water, juice, soda, soda-like beverage) or semisolid food (eg, applesauce, pudding), and stir for a few seconds to blend completely. The prepared mixture should be administered immediately.

SubQ (off-label route): Some experts administer the injectable solution subcutaneously when other routes are unavailable (eg, comfort care settings) (von Gunten 2019).

Rectal (off-label route): Injectable solution may be administered rectally when other routes are unavailable (eg, comfort care settings) (Graves 1987).

Sublingual:

Oral concentrate (off-label route): May be administered sublingually when other routes are unavailable (eg, comfort care settings (Howard 2014).

Oral tablet (off-label route): May be administered sublingually when other routes are unavailable (eg, comfort care settings (Greenblatt 1982).

Sublingual tablet [Canadian product]: Place under tongue; patient should not swallow for at least 2 minutes.

Administration: Pediatric

Oral: May administer with food to decrease GI distress; dilute oral solution in water, juice, soda, or semisolid food (eg, applesauce, pudding).

Intranasal: Administer undiluted (injectable formulation) into one nostril using a needleless syringe or nasal atomizer (Ahmad 2006; Arya 2011)

Parenteral:

IV: Dilute prior to administration. Do not exceed 2 mg/minute or 0.05 mg/kg over 2 to 5 minutes; administer IV using repeated aspiration with slow IV injection, to make sure the injection is not intra-arterial and that perivascular extravasation has not occurred.

IM: Administer undiluted by deep injection into muscle mass

Use: Labeled Indications

Anxiety (oral):

Extended release: Treatment of anxiety disorders in adults who are receiving stable, evenly divided, 3 times daily dosing with lorazepam immediate release.

Immediate release: Management of anxiety disorders or short-term (≤4 months) relief of anxiety.

Procedural anxiety, premedication (injection): Anesthesia premedication in adults to relieve anxiety or to produce amnesia (diminish recall) or sedation.

Status epilepticus (injection): Treatment of status epilepticus. May be used off label for acute seizures that have not yet progressed to status epilepticus.

Use: Off-Label: Adult

Akathisia, antipsychotic-induced; Alcohol withdrawal syndrome; Catatonia; Chemotherapy-induced nausea and vomiting; Intoxication: Cocaine, methamphetamine, and other sympathomimetics; Mechanically ventilated patients in the ICU, sedation; Neuroleptic malignant syndrome; Opioid withdrawal; Serotonin syndrome (serotonin toxicity); Vertigo, acute episodes, treatment

Medication Safety Issues
Sound-alike/look-alike issues:

LORazepam may be confused with ALPRAZolam, clonazePAM, diazePAM, KlonoPIN, Lovaza, temazepam, zolpidem.

Ativan may be confused with Ambien, Atarax, Atgam, Avitene.

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication (IV formulation) among its list of drugs which have a heightened risk of causing significant patient harm when used in error.

Geriatric Patients: High-Risk Medication:

Beers Criteria: Lorazepam is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) because of increased risk of impaired cognition, delirium, falls, fractures, and motor vehicle accidents with benzodiazepine use. However, use may be appropriate in the elderly when used for seizure disorders, rapid eye movement sleep behavior disorders, benzodiazepine or ethanol withdrawal, severe generalized anxiety disorder, or periprocedural anesthesia (Beers Criteria [AGS 2019]).

Administration issues:

Injection dosage form contains propylene glycol. Monitor for toxicity when administering continuous or high-dose lorazepam infusions.

Adverse Reactions (Significant): Considerations
Anterograde amnesia

Benzodiazepines, including lorazepam, can impair explicit memory and produce anterograde amnesia (ie, memory of information or events after drug administration). Retrograde amnesia (ie, events or information prior to drug administration) is unaffected (Ref). Lorazepam has also been reported to produce an atypical effect on implicit memory, disrupt performance on explicit memory tasks, and impair focused attention (Ref).

Mechanism: Dose-related (Ref), although reportedly not a linear dose relationship (Ref). Subjects have shown an inability to transfer events from short-term to long-term memory, therefore interfering with the consolidation process of memories (Ref). Benzodiazepines, including lorazepam, bind to the gamma-aminobutyric acid (GABA)-A receptor, subsequently increasing the frequency of chloride channel opening and producing GABA’s inhibitory effect throughout the CNS. The GABA-A receptor complex has subunits, including a benzodiazepine-binding site, which is classified into several types. The BZ1 receptor type, specifically, which is highly concentrated in the cortex, thalamus, and cerebellum, is responsible for benzodiazepine-associated anterograde amnesia (Ref).

Onset: Rapid

IV administration: Following a single dose of IV lorazepam, a delayed onset of amnesic action of 15 to 30 minutes has been observed, with a duration between 4 to 8 hours. The onset latency is also dose-related, with shorter onset for higher lorazepam doses (ie, 15 minutes after 4 mg) and a longer onset for lower doses (ie, 30 minutes after 2 mg) (Ref).

Risk factors:

• Specific benzodiazepine: Benzodiazepines, such as lorazepam, with a short half-life, rapid onset, and administered IV versus oral, are associated with a high propensity for amnesic effects. However, midazolam is considered to have superior amnestic properties when compared to lorazepam (Ref).

CNS depression

Lorazepam can cause significant drowsiness and sedated state; patients also report having "slowed down thinking" (Ref). In addition, lorazepam has been shown to cause psychomotor impairment by increasing reaction time and decreasing reaction accuracy. Benzodiazepines, in general, are associated with an increased risk of motor vehicle accidents and falls (in older adults) (Ref). Tolerance develops to the sedative effects (Ref).

Mechanism: Dose-dependent (Ref); benzodiazepines, including lorazepam, bind to the gamma-aminobutyric acid (GABA)-A receptor, subsequently increasing the frequency of chloride channel opening and producing GABA’s inhibitory effect throughout the CNS. The GABA-A receptor complex has subunits, including a benzodiazepine-binding site, which is classified into several types. The BZ1 receptor, specifically, which is highly concentrated in the cortex, thalamus, and cerebellum, is responsible for benzodiazepine-associated sedation (Ref).

Onset: Rapid

IV administration: Sedative effects: Due to relatively low lipid solubility, onset of sedation is delayed at 15 to 20 minutes, and may require up to 30 minutes (Ref).

Oral administration: Sedative effects: 20 to 30 minutes (Ref).

Risk factors:

• Older adults (cognitive effects) (Ref)

• Higher doses

• Route of administration (IV administration is associated with a higher risk of sedation versus oral)

Neurodevelopmental effects in children

Animal studies have shown that prolonged or repeated exposure to medications for anesthesia or sedation cause adverse effects on brain maturation resulting in changes in behavior and learning. Some human studies have also suggested similar effects, including epidemiological studies in humans that have observed various cognitive and behavioral problems, including neurodevelopmental delay (and related diagnoses), learning disabilities, and attention deficit hyperactivity disorder. However, data are limited, inconclusive, and further studies are needed to fully characterize findings. Based on the potential risk, the FDA warned in 2016 that in neonates, children <3 years, or patients in the third trimester of pregnancy (ie, times of rapid brain growth and synaptogenesis) undergoing repeated or lengthy exposure to sedatives or anesthetics during surgery/procedures/critical illness, there may be detrimental effects on the child's or fetus’ brain development which may lead to various cognitive and behavioral problems. Relatively short exposure (<3 hours) to sedatives or anesthetics during surgery or procedures is unlikely to adversely affect brain development (Ref).

Mechanism: Unknown; in juvenile animal studies, drugs that potentiate gamma-aminobutyric acid activity and/or block N-methyl-D aspartate receptors for >3 hours demonstrated widespread neuronal and oligodendrocyte cell loss along with alteration in synaptic morphology and neurogenesis (Ref).

Risk factors:

• Neonates, children <3 years, or pregnant patients during their third trimester undergoing procedures lasting >3 hours or multiple procedures (Ref)

Paradoxical reactions

Paradoxical reactions, sometimes referred to as disinhibitory reactions, have been reported in children, adults, and older adults with benzodiazepine use, particularly in those with risk factors. Reactions are relatively uncommon and have been characterized in a number of ways, including increased talkativeness, excitement, restlessness, hyperactivity, sleep disturbances, hostility, rage, agitation, and/or aggressive behavior (Ref). In children, paradoxical reactions to benzodiazepines, particularly midazolam, have been most commonly described as agitation, restlessness, inconsolable crying, screaming, disorientation, and/or excitement (Ref).

Mechanism: Dose-related (potentially, although may also be idiosyncratic); exact mechanism is unclear due to limited evidence (Ref). One hypothesis has suggested that increased GABAergic activity in the brain from benzodiazepines causes a decrease in the restraining influence of the frontal cortex, thereby causing excitement, hostility, and rage. An additional proposed mechanism is that benzodiazepines can reduce 5HT (serotonin) neurotransmission subsequently causing aggressive behavior. Another mechanism is that in select patients with genetic variations in the gamma-aminobutyric acid (GABA) receptor, there is decreased GABA transmission with benzodiazepines which results in neuronal overexcitation manifested clinically as a paradoxical reaction (Ref).

Onset: Rapid; in case reports involving lorazepam, paradoxical reactions occurred within several hours to 24 hours after the first dose; reactions subsided within 24 to 48 hours of discontinuation (Ref)

Risk factors:

Age related (extremes of age):

• Children (Ref)

• Older adults (Ref)

Disease or condition related:

• Past history of aggressive behavior or violence (Ref)

• Alcoholism or history of alcohol use (Ref)

• Psychiatric or personality disorders, including affective disorder (Ref)

• Dementia (Ref)

Patient related:

• Genetic predisposition (potential risk factor) (ie, variability in the density of the GABA-benzodiazepine receptors throughout the brain, a persistence of a juvenile pattern of benzodiazepine response in adulthood, or multiple allelic forms of the receptors with varying affinities for benzodiazepines have all been suggested as potentially playing a role) (Ref)

Medication related: Note: Not established risk factors since evidence is limited (Ref)

• Higher doses (likely a risk, but not firmly established) (Ref)

• Parenteral benzodiazepine administration (potential risk) (Ref)

• Specific benzodiazepines (potential risk): Benzodiazepines with a short half-life and/or those considered to have higher potency (eg, alprazolam, clonazepam, lorazepam, triazolam) compared to lower potency benzodiazepines are believed to increase the risk (Ref)

Propylene glycol toxicity

Propylene glycol, a solvent used in many pharmaceutical preparations, is found in parenteral lorazepam. High doses, continuous use, and/or prolonged use of IV lorazepam can cause propylene glycol accumulation and subsequent toxicity in adults and children, especially low birth-weight infants and those with hepatic or kidney insufficiency (Ref). Propylene glycol accumulation and toxicity is primarily manifested as hyperosmolar metabolic acidosis (ie, a high anion gap metabolic acidosis with elevated osmol gap) and toxicity is associated with acute kidney injury, intravascular hemolysis, hypotension, cardiac arrhythmias, seizures, mental status changes, and CNS depression (Ref). The osmol gap is correlated with serum propylene glycol concentrations and can be used as a surrogate marker to monitor for propylene glycol accumulation and potential toxicity (Ref). Pediatric patients do accumulate propylene glycol but less often display laboratory abnormalities compared to adults (Ref).

Mechanism: Dose-related; propylene glycol is oxidized by alcohol dehydrogenase to lactaldehyde, which is metabolized by aldehyde dehydrogenase to lactic acid. The accumulation of lactic acid results in metabolic acidosis, but is usually well tolerated. Lactate in this scenario is not generated from any underlying pathology. The lactate is oxidized to pyruvate and then is metabolized by the normal carbohydrate processes.

Onset: Rapid; propylene glycol accumulation, as evidenced by a hyperosmolar anion gap metabolic acidosis, has been observed as early as 48 hours following high-dose continuous infusions (mean lorazepam dose: 8.1 mg/kg; mean infusion rate: 0.16 mg/kg/hour) (Ref).

Risk factors:

Duration: Continuous infusions >48 hours in adults (Ref)

Dose: High continuous doses of IV lorazepam (doses exceeding recommended adult dosage range of 0.1 mg/kg/hour in critically ill patients) (Ref)

• Kidney dysfunction (propylene glycol is excreted unchanged in the urine) (Ref)

• Hepatic dysfunction (Ref)

• Concomitant medications also containing propylene glycol (eg, diazepam, esmolol, nitroglycerin, phenytoin, phenobarbital, sulfamethoxazole/trimethoprim) (Ref)

• Impaired alcohol dehydrogenase enzyme system (eg, young children) (Ref)

• Concomitant disulfiram or metronidazole (Ref)

• Alcohol use disorder (Ref)

• Pregnancy (Ref)

• Propylene glycol concentrations exceeding 25 mg/dL. Note: Serum propylene glycol concentrations are difficult to obtain in most clinical settings and test turnaround time is slow; osmol gap is recommended as a surrogate marker (Ref).

• In the absence of other osmotic agents (eg, alcohols), an osmol gap of ≥10 was predictive of elevated propylene glycol concentrations; values of ≥12 suggest propylene glycol toxicity (Ref).

• Critically ill neonates, especially those weighing <5 kg (Ref)

• Neonates receiving large amounts of propylene glycol orally, IV (eg, >3,000 mg/day), or topically (Ref)

Withdrawal syndrome

Therapeutic use of benzodiazepines, including lorazepam, is associated with a withdrawal syndrome in children and adults, particularly following abrupt or overly rapid discontinuation. Withdrawal symptoms can include new withdrawal symptoms or rebound symptoms, both of which are typically transient, short-lasting, and reversible. A persistent post-withdrawal disorder, which can be long-lasting, severe, and potentially irreversible, has also been described. In general, withdrawal symptoms are typically mild and characterized as anxiety, panic attacks, restlessness, insomnia and other sleep disturbances, irritability, poor concentration, confusion, nausea/vomiting, weight loss, tremor, diaphoresis, tachycardia, and muscle pain/stiffness. Severe symptoms such as seizure and psychosis may also rarely occur following abrupt discontinuation. Severe withdrawal may be fatal. Data are limited on persistent post-withdrawal disorders, but cognitive impairment, depression, anxiety, sensory disturbances (eg, tinnitus, paresthesia, skin sensations), motor disturbances (eg, muscle pain, weakness, spasms), and GI disturbances have been described (Ref). There are also rare case reports of new-onset mania occurring after abrupt withdrawal of chronic lorazepam (Ref). New withdrawal symptoms typically resolve within 2 to 4 weeks and rebound symptoms may last 3 weeks, but persistent post-withdrawal symptoms may last >6 weeks and take 6 to 12 months to completely resolve, and in some cases, persist for years. Severity, onset, and duration of any benzodiazepine withdrawal syndrome varies based on several factors, such as specific benzodiazepine administered (and its half -life), dose, and duration of use (Ref).

Mechanism: Withdrawal; exact mechanisms are complex and unclear, but chronic exposure to benzodiazepines alters GABAergic neurotransmission (up/down regulation of gamma-aminobutyric acid [GABA]-A receptor subunits) and rapid or abrupt withdrawal results in underactivity of inhibitory GABA functions subsequently increasing excitatory nervous activity and likely contributing to symptoms associated with withdrawal (Ref). A role of glutamate receptors, including N-methyl-D aspartate (NMDA)-, non-NMDA-receptors, and metabotropic glutamate (mGlu) receptors, has also been suggested. In mice and rat studies, antagonists for NMDA, non-NMDA, and group 1 mGluRs have shown the ability to potently suppress the withdrawal signs caused by chronic benzodiazepine administration (Ref).

Onset: Varied; onset of symptoms usually occurs within the first day following abrupt withdrawal of lorazepam and any other short- or intermediate-acting benzodiazepines. Long-acting benzodiazepines (eg, diazepam) are associated with an initial onset of withdrawal symptoms 5 days following abrupt discontinuation (Ref). In general, persistent post-withdrawal disorder associated with psychotropic medications have an onset ranging from 24 hours to 6 weeks following a decrease, discontinuation, or switch (Ref).

Risk factors:

• Abrupt discontinuation (rather than gradual dosage reduction) of a benzodiazepine used long-term (Ref)

• Higher doses (Ref)

• Chronic dosing (ie, intermittent dosing may reduce the risk of withdrawal symptoms) (Ref).

• Withdrawal-associated seizure: Predisposed patients (eg, brain damage, alcohol abuse, history of seizure, or those receiving agents that lower the seizure threshold) (Ref)

• Specific benzodiazepine: High-potency benzodiazepines with short to intermediate half-lives, such as lorazepam, are more frequently associated with withdrawal symptoms; benzodiazepines with a short and intermediate half-life have a higher risk for rebound, withdrawal reactions, and dependence compared to long-acting benzodiazepines (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Local: Pain at injection site (IM: 1% to 17%; IV: 2%)

Nervous system: Drowsiness, sedated state

1% to 10%:

Cardiovascular: Hypotension (≤2%)

Local: Erythema at injection site (2%)

Nervous system: Coma (≤1%), confusion (≤1%), delirium (≤1%), depression (≤1%), dizziness (7%), excessive crying (≤1%), hallucinations (1%), headache (≤1%), restlessness (≤1%), stupor (≤1%), unsteadiness (3%)

Neuromuscular & skeletal: Asthenia (≤4%)

Respiratory: Apnea (1%), hypoventilation (≤1%), respiratory failure (2%)

<1%:

Cardiovascular: Hypertension

Endocrine & metabolic: Acidosis

Gastrointestinal: Nausea, sialorrhea, vomiting

Genitourinary: Cystitis

Hematologic & oncologic: Thrombocytopenia

Hepatic: Abnormal hepatic function tests, increased serum alkaline phosphatase

Infection: Infection

Local: Injection site reaction

Nervous system: Abnormal gait, abnormality in thinking, agitation, ataxia, brain edema, chills, myoclonus, seizure

Neuromuscular & skeletal: Tremor

Otic: Hearing loss

Respiratory: Hyperventilation

Frequency not defined:

Dermatologic: Alopecia, skin rash

Endocrine & metabolic: Change in libido, hyponatremia, increased lactate dehydrogenase, SIADH

Gastrointestinal: Changes in appetite, constipation

Genitourinary: Impotence, orgasm disturbance

Hematologic & oncologic: Agranulocytosis, leukopenia, pancytopenia

Hepatic: Increased serum bilirubin, increased serum transaminases, jaundice

Hypersensitivity: Anaphylaxis, hypersensitivity reaction

Nervous system: Disinhibition, disorientation, drug dependence, dysarthria, dysautonomia, euphoria, extrapyramidal reaction, fatigue, hypothermia, memory impairment, sleep apnea (exacerbation), slurred speech, suicidal ideation, suicidal tendencies, vertigo, withdrawal syndrome

Ophthalmic: Visual disturbance

Respiratory: Exacerbation of chronic obstructive pulmonary disease, respiratory depression

Miscellaneous: Paradoxical reaction (Mancuso 2004)

Postmarketing:

Cardiovascular: Bradycardia, cardiac arrhythmia, cardiac failure, heart block, pericardial effusion, prolonged QT interval on ECG (Ziegenbein 2004), tachycardia, ventricular arrhythmia

Endocrine & metabolic: Pheochromocytoma (aggravation)

Gastrointestinal: Gastrointestinal hemorrhage

Genitourinary: Urinary incontinence

Hematologic & oncologic: Disorder of hemostatic components of blood, pulmonary hemorrhage

Hepatic: Hepatotoxicity

Hypersensitivity: Fixed drug eruption (Agulló-García 2018)

Nervous system: Aggressive behavior (Bond 1988, Pietras 2005), anterograde amnesia (Pandit 1976), nervousness, neuroleptic malignant syndrome, paralysis

Ophthalmic: Blurred vision, diplopia (Lucca 2014)

Respiratory: Pneumothorax, pulmonary edema, pulmonary hypertension

Miscellaneous: Propylene glycol toxicity (IV) (Neale 2005)

Contraindications

Hypersensitivity to lorazepam, any component of the formulation, or other benzodiazepines (cross-sensitivity with other benzodiazepines may exist); acute narrow-angle glaucoma.

Parenteral: Additional contraindications: Hypersensitivity to polyethylene glycol, propylene glycol, or benzyl alcohol; sleep apnea; intra-arterial injection; use in premature infants; severe respiratory insufficiency (except during mechanical ventilation).

Canadian labeling: Additional contraindications (not in the US labeling): Myasthenia gravis.

Warnings/Precautions

Concerns related to adverse effects:

• Sleep-related activities: Hazardous sleep-related activities, such as sleep-driving, cooking and eating food, and making phone calls while asleep, have been noted with benzodiazepines (Dolder 2008).

Disease-related concerns:

• Depression: Use caution in patients with depression, particularly if suicidal risk may be present.

• Hepatic impairment: Use with caution in patients with hepatic impairment, insufficiency, and/or encephalopathy. Dose adjustment (lower doses) may be needed. May worsen hepatic encephalopathy.

• Renal impairment: Use with caution in patients with renal impairment.

• Respiratory disease: Use with caution in patients with respiratory disease, including chronic obstructive pulmonary disease or sleep apnea. Benzodiazepines may cause significant respiratory depression.

Concurrent drug therapy issues:

• Concomitant use with opioids: In patients already receiving an opioid analgesic, prescribe a lower initial dose of lorazepam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking lorazepam, prescribe a lower initial dose of the opioid and titrate based upon clinical response.

• Flumazenil: Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.

Special populations:

• Debilitated patients: Use with caution in debilitated patients; initial doses should be at the lower end of dosing range.

• Elderly patients: Elderly patients may be at an increased risk of death with use; risk has been found highest within the first 4 months of use in elderly dementia patients (Jennum 2015; Saarelainen 2018).

• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury (Nelson 1999).

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein-binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.

• Polyethylene glycol: Parenteral formulation may contain polyethylene glycol. May be associated with toxicity in high-dose and/or longer-term therapy.

• Tartrazine: Some formulations may contain tartrazine (FD&C Yellow No. 5), which may cause allergic-type reactions (including bronchial asthma) in susceptible individuals, particularly those who also have aspirin sensitivity.

Other warnings/precautions:

• Abuse, misuse, and addiction: Counsel patients at increased risk on proper use and monitoring for signs and symptoms of abuse, misuse, and addiction. Institute early treatment or refer patients in whom substance use disorder is suspected. Limit dosages and durations to the minimum required.

• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties. Status epilepticus should not be treated with injectable benzodiazepines alone; requires close observation and management and possibly ventilatory support. When used as a component of preanesthesia, monitor for heavy sedation and airway obstruction; equipment necessary to maintain airway and ventilatory support should be available.

• Tolerance: Lorazepam is a short half-life benzodiazepine. Duration of action after a single dose is determined by redistribution rather than metabolism. Tolerance develops to the sedative, hypnotic, and antiseizure effects. It does not develop to the anxiolytic effects (Vinkers 2012). Chronic use of this agent may increase the perioperative benzodiazepine dose needed to achieve desired effect.

Warnings: Additional Pediatric Considerations

In pediatric and neonatal patients <3 years of age and patients in third trimester of pregnancy (ie, times of rapid brain growth and synaptogenesis), the repeated or lengthy exposure to sedatives or anesthetics during surgery/procedures may have detrimental effects on the child's or fetus’ brain development and may contribute to various cognitive and behavioral problems; the FDA is requiring warnings be included in the manufacturer's labeling for all general anesthetic/sedative drugs. Multiple animal species studies have shown adverse effects on brain maturation; in juvenile animals, drugs that potentiate GABA activity and/or block NMDA receptors for >3 hours demonstrated widespread neuronal and oligodendrocyte cell loss along with alteration in synaptic morphology and neurogenesis. Epidemiological studies in humans have reported various cognitive and behavioral problems including neurodevelopmental delay (and related diagnoses), learning disabilities, and ADHD. Human clinical data suggest that single, relatively short exposures are not likely to have similar negative effects. Further studies are needed to fully characterize findings and ensure that these findings are not related to underlying conditions or the procedure itself. No specific anesthetic/sedative has been found to be safer. For elective procedures, risk vs benefits should be evaluated and discussed with parents/caregivers/patients; critical surgeries should not be delayed (FDA 2016).

Use with caution in neonates, especially in preterm infants; several cases of neurotoxicity and myoclonus (rhythmic myoclonic jerking) have been reported. Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines, particularly in pediatric/adolescent or psychiatric patients; discontinue drug if this occurs.

Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).

Metabolism/Transport Effects

None known.

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

CloZAPine: Benzodiazepines may enhance the adverse/toxic effect of CloZAPine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Risk D: Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Loxapine: May enhance the adverse/toxic effect of LORazepam. Specifically, prolonged stupor, respiratory depression, and/or hypotension. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Melatonin: May enhance the sedative effect of Benzodiazepines. Risk C: Monitor therapy

Methadone: Benzodiazepines may enhance the CNS depressant effect of Methadone. Management: Clinicians should generally avoid concurrent use of methadone and benzodiazepines when possible; any combined use should be undertaken with extra caution. Risk D: Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

MetroNIDAZOLE (Systemic): May enhance the adverse/toxic effect of Products Containing Propylene Glycol. A disulfiram-like reaction may occur. Risk X: Avoid combination

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

OLANZapine: Benzodiazepines may enhance the adverse/toxic effect of OLANZapine. Management: Monitor closely for hypotension, respiratory or central nervous system depression, and bradycardia if olanzapine is combined with benzodiazepines. Use of parenteral benzodiazepines with IM olanzapine is not recommended. Risk C: Monitor therapy

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: Benzodiazepines may enhance the CNS depressant effect of Oxybate Salt Products. Risk X: Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Probenecid: May increase the serum concentration of LORazepam. Management: Reduce lorazepam dose 50% during coadministration with probenecid. Monitor for increased and prolonged lorazepam effects, particularly CNS depressant effects. Patients using lorazepam ER capsules should be switched to lorazepam tablets. Risk D: Consider therapy modification

Pyrimethamine: LORazepam may enhance the hepatotoxic effect of Pyrimethamine. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Secnidazole: Products Containing Propylene Glycol may enhance the adverse/toxic effect of Secnidazole. Risk X: Avoid combination

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Teduglutide: May increase the serum concentration of Benzodiazepines. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk C: Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

UGT2B15 Inhibitors: May increase the serum concentration of LORazepam. Management: Avoid coadministration of UGT2B15 inhibitors and extended release lorazepam capsules. If coadministration is required, discontinue lorazepam extended release capsules and use lorazepam tablets instead. Monitor for increased lorazepam toxicities. Risk D: Consider therapy modification

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Valproate Products: May increase the serum concentration of LORazepam. Management: Reduce lorazepam dose 50% during coadministration with valproate products. Monitor for increased lorazepam effects, particularly CNS depression. Patients taking lorazepam extended-release capsules should be switched to lorazepam tablets. Risk D: Consider therapy modification

Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Pregnancy Considerations

Lorazepam and its metabolite cross the human placenta. Teratogenic effects in humans have been observed with some benzodiazepines (including lorazepam); however, additional studies are needed. The incidence of premature birth and low birth weights may be increased following maternal use of benzodiazepines; hypoglycemia and respiratory problems in the neonate may occur following exposure late in pregnancy. Neonatal withdrawal symptoms may occur within days to weeks after birth and “floppy infant syndrome” (which also includes withdrawal symptoms) have been reported with some benzodiazepines (including lorazepam). Elimination of lorazepam in the newborn infant is slow; following in utero exposure, term infants may excrete lorazepam for up to 8 days (Bergman 1992; Iqbal 2002; Wikner 2007).

Breastfeeding Considerations

Lorazepam is present in breast milk.

The relative infant dose (RID) of lorazepam is 2.4% to 4.7% when calculated using the highest breast milk concentration located following benzodiazepine monotherapy with lorazepam and compared to an infant therapeutic dose of 0.15 to 0.3 mg/kg/day (0.05 mg/kg/dose every 4 to 8 hours). In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000); however, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Larsen 2015). Using the highest total milk concentration (12 mcg/L free lorazepam plus 35 mcg/L conjugated lorazepam), the estimated the daily infant dose via breast milk is 7.05 mcg/kg/day. These milk concentrations were obtained following maternal administration of oral lorazepam 2.5 mg twice daily for the first five days postpartum; the mother had begun treatment with lorazepam prior to delivery (route, dose, and duration not specified) (Whitelaw 1981). Higher milk concentrations were observed in one mother who received both oral lorazepam and lormetazepam, which is partially metabolized to lorazepam (Lemmer 2007).

In general, sedation, lethargy, irritability, poor weight gain, and apnea have been reported in breastfed infants exposed to benzodiazepines; however, these adverse effects were not observed in breastfed infants exposed to lorazepam (Kelly 2012). The manufacturer warns of the potential for sedation, irritability, and impaired suckling in the infant. Monitor breastfed infants for drowsiness (WHO 2002).

Although the manufacturer recommends that lorazepam should not be administered to breastfeeding women unless the expected benefit to the woman outweighs the potential risk to the infant, short-acting benzodiazepines, including lorazepam, are considered compatible with breastfeeding (Kelly 2012; WHO 2002). When possible, limit exposure to single doses (WHO 2002).

Monitoring Parameters

Respiratory and cardiovascular status, BP, heart rate, symptoms of anxiety, mental alertness.

Long-term therapy: CBC, liver function tests, LDH.

High-dose or continuous IV use or IV use in patients with renal impairment: Clinical signs of propylene glycol toxicity, serum creatinine, BUN, serum lactate, osmol gap; Note: An osmol gap of ≥10 was predictive of elevated propylene glycol concentrations; values of ≥12 suggest propylene glycol toxicity (Arroliga 2004; Barnes 2006; Yahwak 2008).

Critically ill patients: Assess and adjust sedation according to scoring system (Richmond Agitation-Sedation Scale [RASS] or Sedation-Agitation Scale [SAS]) (SCCM [Devlin 2018]).

Mechanism of Action

Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization. Benzodiazepine receptors and effects appear to be linked to the GABA-A receptors. Benzodiazepines do not bind to GABA-B receptors.

Pharmacokinetics

Onset of action:

Antiseizure medication: IV: Within 10 minutes.

Hypnosis: IM: 20 to 30 minutes.

Sedation:

IV: 15 to 20 minutes (dose dependent) (Barr 2013; Horn 2004).

Oral: 20 to 30 minutes (Horn 2004).

Duration: Anesthesia premedication: Adults: IM, IV: ~6 to 8 hours.

Absorption: IM: Rapid and complete absorption; Oral: Readily absorbed.

Distribution:

Neonates: IV: Vd: 0.76 ± 0.37 L/kg (range: 0.14 to 1.3 L/kg) (McDermott 1992).

Pediatric patients (Chamberlain 2012): IV: Vd:

5 months to <3 years: 1.62 L/kg (range: 0.67 to 3.4 L/kg).

3 to <13 years: 1.5 L/kg (range: 0.49 to 3 L/kg).

13 to <18 years: 1.27 L/kg (range: 1 to 1.54 L/kg).

Adults:

IV: Vd: 1.3 L/kg.

Oral: Extended release: Vd: 117 L.

Protein binding: 85% to 91%.

Metabolism: Hepatic; rapidly conjugated to lorazepam glucuronide (inactive).

Bioavailability: Oral: 90%.

Half-life elimination:

Full-term neonates: IV: 40.2 ± 16.5 hours; range: 18 to 73 hours (McDermott 1992).

Pediatric patients (Chamberlain 2012): IV:

5 months to <3 years: 15.8 hours (range: 5.9 to 28.4 hours).

3 to <13 years: 16.9 hours (range: 7.5 to 40.6 hours).

13 to <18 years: 17.8 hours (range: 8.2 to 42 hours).

Adults: Oral: Extended release: ~20.2 ± 7.2 hours; Immediate release: ~12 hours; IV: ~14 hours; IM: ~13 to 18 hours (Greenblatt 1983); End-stage renal disease (ESRD): ~18 hours.

Time to peak:

IM: ≤3 hours.

Oral:

Extended release: 14 hours (range: 7 to 24 hours).

Immediate release: ~2 hours.

Sublingual tablet [Canadian product]: 1 hour.

Excretion: Urine (~88%; predominantly as inactive metabolites); feces (~7%).

Pricing: US

Capsule ER 24 Hour Sprinkle (Loreev XR Oral)

1 mg (per each): $11.40

2 mg (per each): $11.40

3 mg (per each): $11.40

Concentrate (LORazepam Intensol Oral)

2 mg/mL (per mL): $1.60

Concentrate (LORazepam Oral)

2 mg/mL (per mL): $1.33 - $1.60

Solution (Ativan Injection)

2 mg/mL (per mL): $2.28

4 mg/mL (per mL): $3.17

Solution (LORazepam Injection)

2 mg/mL (per mL): $0.62 - $4.06

4 mg/mL (per mL): $2.16 - $3.40

Tablets (Ativan Oral)

0.5 mg (per each): $37.26

1 mg (per each): $49.77

2 mg (per each): $79.32

Tablets (LORazepam Oral)

0.5 mg (per each): $0.07 - $0.68

1 mg (per each): $0.07 - $0.88

2 mg (per each): $0.09 - $1.28

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Amparax (CL);
  • Ansilor (PT);
  • Anta (TH);
  • Anxiar (RO);
  • Anxira (TH);
  • Anzepam (TW);
  • Aplacasse (AR);
  • Ativan (AE, AU, BB, BF, BJ, CI, CO, ET, GB, GH, GM, GN, HK, IE, IN, JO, KE, KR, KW, LR, MA, ML, MR, MT, MU, MW, MX, NE, NG, NZ, PE, PK, SA, SC, SD, SL, SN, TN, TR, TW, TZ, UG, UY, VE, VN, ZA, ZM, ZW);
  • Bonatranquan (DE);
  • Control (IT);
  • Donix (ES);
  • Emotival (AR);
  • Larpose (IN, LK);
  • Laubeel (DE);
  • Lauracalm (LU);
  • Lonza (TH);
  • Lopa (BD);
  • Lopam (TW);
  • Lora (CN);
  • Lora-Pita (JP);
  • Lorafen (LV, PL);
  • Loram (HR);
  • Lorans (AE, CY, EG, HK, IQ, IR, IT, JO, KW, LB, LT, LY, MT, MY, OM, SA, SY, YE);
  • Loranxil (HU);
  • Loravan (KR);
  • Lorax (BR);
  • Loraxen (BD);
  • Lorazep (TH);
  • Lorazepam-Efeka (LU);
  • Lorazepam-Eurogenerics (LU);
  • Lorazin (TW);
  • Lorenin (PT);
  • Loridem (LU);
  • Lorivan (HK, IL, MT);
  • Lorsedal (PT);
  • Lorsilan (HR);
  • Lozam (CR, DO, GT, HN, NI, PA, SV);
  • Lozicum (BD, HK);
  • Merlopam (ID);
  • Nervistop L (AR);
  • Neuropam (TW);
  • Novhepar (GR);
  • Orfidal (ES);
  • Renaquil (ID);
  • Rilex (HU);
  • Serenase (BE);
  • Sidenar (AR);
  • Silence (HK, TW);
  • Sinestron (CR, DO, GT, HN, NI, PA, SV);
  • Stapam (TW);
  • Tavor (BG, DE, GR, IT);
  • Temesta (AT, BE, CH, DK, FI, FR, LU, NL, SE);
  • Titus (AE, BF, BJ, CI, CY, EG, ET, GH, GM, GN, GR, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, SA, SC, SD, SL, SN, SY, TN, TZ, UG, YE, ZM, ZW);
  • Tranqipam (ZA);
  • Trapax (AR, PY);
  • Trapex (BD, IN);
  • Vigiten (LU)


For country abbreviations used in Lexicomp (show table)

REFERENCES

  1. 2019 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 Updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694. doi: 10.1111/jgs.15767. [PubMed 30693946]
  2. Adler L, Angrist B, Peselow E, Corwin J, Rotrosen J. Efficacy of propranolol in neuroleptic-induced akathesia. J Clin Psychopharmacol. 1985;5(3):164-166. [PubMed 2860136]
  3. Agulló-García A, Garcés Sotillos M, Colás Sanz C. Fixed drug eruption due to lorazepam. J Investig Allergol Clin Immunol. 2018;28(3):185-186. doi:10.18176/jiaci.0225 [PubMed 29939135]
  4. Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr. 2001;139(2):317-319. [PubMed 11487763]
  5. Ahmad S, Ellis JC, Kamwendo H, Molyneux E. Efficacy and safety of intranasal lorazepam versus intramuscular paraldehyde for protracted convulsions in children: an open randomised trial. Lancet. 2006;367(9522):1591-1597. [PubMed 16698412]
  6. Akerele E, Olupona T. Drugs of abuse. Psychiatr Clin North Am. 2017;40(3):501-517. doi: 10.1016/j.psc.2017.05.006. [PubMed 28800805]
  7. American Society of Addiction Medicine (ASAM). The ASAM clinical practice guideline on alcohol withdrawal management. J Addict Med. 2020:14(3S)(suppl 1):1-72. doi:10.1097/ADM.0000000000000668 [PubMed 32511109]
  8. Amini A, Heidari K, Asadollahi S, et al. Intravenous promethazine versus lorazepam for the treatment of peripheral vertigo in the emergency department: A double blind, randomized clinical trial of efficacy and safety. J Vestib Res. 2014;24(1):39-47. doi: 10.3233/VES-130506. [PubMed 24594499]
  9. Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther. 2016;100(1):42-52. [PubMed 27060684]
  10. Apo-Lorazepam [product monograph]. Toronto, Ontario, Canada: Apotex Inc; August 2013.
  11. Arnold TC, Ryan ML. Acute amphetamine and synthetic cathinone ("bath salt") intoxication. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed April 30, 2019.
  12. Aronoff GR, Bennett WM, Berns JS, et al, eds. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children. 5th ed. Philadelphia, PA: American College of Physicians; 2007:126, 182.
  13. Arroliga AC, Shehab N, McCarthy K, Gonzales JP. Relationship of continuous infusion lorazepam to serum propylene glycol concentration in critically ill adults. Crit Care Med. 2004;32(8):1709-1714. [PubMed 15286548]
  14. Arya R, Gulati S, Kabra M, Sahu JK, Kalra V. Intranasal versus intravenous lorazepam for control of acute seizures in children: a randomized open-label study. Epilepsia. 2011;52(4):788-793. [PubMed 21275979]
  15. Ativan (lorazepam) [product monograph]. Kirkland, Quebec, Canada: Pfizer Canada ULC; May 2021.
  16. Ativan (lorazepam) injection [prescribing information]. Berkeley Heights, NJ: Hikma Pharmaceuticals USA Inc; February 2021.
  17. Ativan (lorazepam) tablet [prescribing information]. Bridgewater, NJ: Bausch Health US LLC; February 2021.
  18. Authier N, Balayssac D, Sautereau M, et al. Benzodiazepine dependence: focus on withdrawal syndrome. Ann Pharm Fr. 2009;67(6):408-413. doi:10.1016/j.pharma.2009.07.001 [PubMed 19900604]
  19. Bahn EL, Holt KR. Procedural sedation and analgesia: a review and new concepts. Emerg Med Clin North Am. 2005;23(2):503-517. doi:10.1016/j.emc.2004.12.013 [PubMed 15829394]
  20. Bandelow B, Zohar J, Hollander E, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders - first revision. World J Biol Psychiatry. 2008;9(4):248-312. doi: 10.1080/15622970802465807. [PubMed 18949648]
  21. Barnes BJ, Gerst C, Smith JR, Terrell AR, Mullins ME. Osmol gap as a surrogate marker for serum propylene glycol concentrations in patients receiving lorazepam for sedation. Pharmacotherapy. 2006;26(1):23-33. [PubMed 16422667]
  22. Barr J, Fraser GL, Puntillo K, et al; American College of Critical Care Medicine. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306. doi:10.1097/CCM.0b013e3182783b72 [PubMed 23269131]
  23. Bartels M, Heide K, Mann K, Schied HW. Treatment of akathisia with lorazepam. An open clinical trial. Pharmacopsychiatry. 1987;20(2):51-53. doi: 10.1055/s-2007-1017074. [PubMed 2884681]
  24. Basura GJ, Adams ME, Monfared A, et al. Clinical practice guideline: Ménière's disease. Otolaryngol Head Neck Surg. 2020;162(2 suppl):S1-S55. doi:10.1177/0194599820909438 [PubMed 32267799]
  25. Becker DE. Pharmacodynamic considerations for moderate and deep sedation. Anesth Prog. 2012;59(1):28-42. doi:10.2344/0003-3006-59.1.28 [PubMed 22428972]
  26. Bergman U, Rosa FW, Baum C, et al. Effects of exposure to benzodiazepine during fetal life, Lancet, 1992;340(8821):694-696. [PubMed 1355799]
  27. Bhattacharyya N, Gubbels SP, Schwartz SR, et al. Clinical practice guideline: benign paroxysmal positional vertigo (update). Otolaryngol Head Neck Surg. 2017;156(3)(suppl):S1-S47. doi: 10.1177/0194599816689667. [PubMed 28248609]
  28. Blin O, Simon N, Jouve E, et al. Pharmacokinetic and pharmacodynamic analysis of sedative and amnesic effects of lorazepam in healthy volunteers. Clin Neuropharmacol. 2001;24(2):71-81. doi:10.1097/00002826-200103000-00002 [PubMed 11307041]
  29. Bond A, Lader M. Differential effects of oxazepam and lorazepam on aggressive responding. Psychopharmacology (Berl). 1988;95(3):369-373. doi:10.1007/BF00181949 [PubMed 3137624]
  30. Boyer EW. Serotonin syndrome (serotonin toxicity). Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed May 5, 2020.
  31. Boyer EW, Seifert SA, Hernon C. Methamphetamine: Acute intoxication. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed April 30, 2019b.
  32. Brophy GM, Bell R, Claassen J, et al; Neurocritical Care Society Status Epilepticus Guideline Writing Committee. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3-23. [PubMed 22528274]
  33. Bulathsinghala M, Keefer K, Van de Louw A. Trimethoprim/Sulfamethoxazole-induced severe lactic acidosis: A case report and review of the literature. Medicine (Baltimore). 2016;95(17):e3478. doi:10.1097/MD.0000000000003478 [PubMed 27124045]
  34. Burtles R, Astley B. Lorazepam in children. A double-blind trial comparing lorazepam, diazepam, trimeprazine and placebo. Br J Anaesth. 1983;55(4):275-279. [PubMed 6132612]
  35. Bush G, Fink M, Petrides G, Dowling F, Francis A. Catatonia. II. Treatment with lorazepam and electroconvulsive therapy. Acta Psychiatr Scand. 1996;93(2):137-143. [PubMed 8686484]
  36. Busto U, Sellers EM, Naranjo CA, Cappell H, Sanchez-Craig M, Sykora K. Withdrawal reaction after long-term therapeutic use of benzodiazepines. N Engl J Med. 1986;315(14):854-859. doi:10.1056/NEJM198610023151403 [PubMed 3092053]
  37. Caillé G, Spénard J, Lacasse Y, Brennan J. Pharmacokinetics of two lorazepam formulations, oral and sublingual, after multiple doses. Biopharm Drug Dispos. 1983;4(1):31-42. doi: 10.1002/bdd.2510040106. [PubMed 6132630]
  38. Cammarano WB, Pittet JF, Weitz S, Schlobohm RM, Marks JD. Acute withdrawal syndrome related to the administration of analgesic and sedative medications in adult intensive care unit patients. Crit Care Med. 1998;26(4):676-84. doi:10.1097/00003246-199804000-00015 [PubMed 9559604]
  39. Carson SS, Kress JP, Rodgers JE, et al. A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients. Crit Care Med. 2006;34(5):1326-1332. doi: 10.1097/01.CCM.0000215513.63207.7F. [PubMed 16540958]
  40. Centers for Disease Control (CDC). Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982;31(22):290-291. http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm [PubMed 6810084]
  41. Cernaianu AC, DelRossi AJ, Flum DR, et al. Lorazepam and midazolam in the intensive care unit: a randomized, prospective, multicenter study of hemodynamics, oxygen transport, efficacy, and cost. Crit Care Med. 1996;24(2):222-228. doi: 10.1097/00003246-199602000-00007. [PubMed 8605792]
  42. Chamberlain JM, Capparelli EV, Brown KM, et al. Pharmacokinetics of intravenous lorazepam in pediatric patients with and without status epilepticus. J Pediatr. 2012;160(4):667-672. [PubMed 22050870]
  43. Chang DH, Hiss S, Herich L, et al. Implantation of venous access devices under local anesthesia: patients' satisfaction with oral lorazepam. Patient Prefer Adherence. 2015;9:943-949. doi: 10.2147/PPA.S80330. [PubMed 26185424]
  44. Chicella M, Jansen P, Parthiban A, et al. Propylene glycol accumulation associated with continuous infusion of lorazepam in pediatric intensive care patients. Crit Care Med. 2002;30(12):2752-2756. doi:10.1097/00003246-200212000-00021 [PubMed 12483068]
  45. Chouinard G. Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J Clin Psychiatry. 2004;65(suppl 5):7-12. [PubMed 15078112]
  46. Choy Y. Treatment of acute procedural anxiety in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed April 30, 2019.
  47. Cloherty JP, Eichenwald EC, Stark AR, eds. Manual of Neonatal Care. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.
  48. Coffey MJ. Catatonia in adults: Epidemiology, clinical features, assessment, and diagnosis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed July 26, 2021a.
  49. Coffey MJ. Catatonia: Treatment and prognosis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed April 15, 2021b.
  50. Cosci F, Chouinard G. Acute and persistent withdrawal syndromes following discontinuation of psychotropic medications. Psychother Psychosom. 2020;89(5):283-306. doi:10.1159/000506868 [PubMed 32259826]
  51. Craske M, Bystritsky A. Generalized anxiety disorder in adults: management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed November 15, 2021.
  52. Crawford TO, Mitchell WG, Snodgrass SR. Lorazepam in Childhood Status Epilepticus and Serial Seizures: Effectiveness and Tachyphylaxis. Neurology. 1987;37(2):190-195. [PubMed 3808299]
  53. Curran HV. Benzodiazepines, memory and mood: a review. Psychopharmacology (Berl). 1991;105(1):1-8. doi:10.1007/BF02316856 [PubMed 1684055]
  54. Curran HV, Schiwy W, Lader M. Differential amnesic properties of benzodiazepines: a dose-response comparison of two drugs with similar elimination half-lives. Psychopharmacology (Berl). 1987;92(3):358-364. doi:10.1007/BF00210844 [PubMed 3114788]
  55. Daniels J. Catatonia: clinical aspects and neurobiological correlates. J Neuropsychiatry Clin Neurosci. 2009;21(4):371-380. doi:10.1176/appi.neuropsych.21.4.371. [PubMed 19996245]
  56. Dawson J, Boyle J, Stanley N, Johnsen S, Hindmarch I, Skene DJ. Benzodiazepine-induced reduction in activity mirrors decrements in cognitive and psychomotor performance. Hum Psychopharmacol. 2008;23(7):605-613. doi:10.1002/hup.961 [PubMed 18570226]
  57. Department of Veterans Affairs/Department of Defense. Clinical Practice Guideline for the Management of Substance Use Disorders. https://www.healthquality.va.gov/guidelines/MH/sud/VADoDSUDCPGRevised22216.pdf. Published December 2015. Accessed May 2019.
  58. Deshmukh A, Wittert W, Schnitzler E, Mangurten HH. Lorazepam in the treatment of refractory neonatal seizures. A pilot study. Am J Dis Child. 1986;140(10):1042-1044. [PubMed 3752014]
  59. Devlin JW, Skrobik Y, Gélinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46(9):e825-e873. doi: 10.1097/CCM.0000000000003299. [PubMed 30113379]
  60. Díaz-Gutiérrez MJ, Martínez-Cengotitabengoa M, Sáez de Adana E, et al. Relationship between the use of benzodiazepines and falls in older adults: A systematic review. Maturitas. 2017;101:17-22. doi:10.1016/j.maturitas.2017.04.002 [PubMed 28539164]
  61. Dolder CR, Nelson MH. Hypnosedative-induced complex behaviours: incidence, mechanisms and management. CNS Drugs. 2008;22(12):1021-1036. doi:10.2165/0023210-200822120-00005. [PubMed 18998740]
  62. Dominguez KD, Crowley MR, Coleman DM, Katz RW, Wilkins DG, Kelly HW. Withdrawal from lorazepam in critically ill children. Ann Pharmacother. 2006;40(6):1035-1039. doi:10.1345/aph.1G701 [PubMed 16720707]
  63. Drappatz J, Avila EK. Seizures in patients with primary and metastatic brain tumors. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed April 15, 2019.
  64. Drislane FW. Convulsive status epilepticus in adults: Treatment and prognosis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed May 5, 2020.
  65. Dupuis LL, Nathan PC. Options for the prevention and management of acute chemotherapy-induced nausea and vomiting in children. Paediatr Drugs. 2003;5(9):597-613. [PubMed 12956617]
  66. Dupuis LL, Robinson PD, Boodhan S, et al; Pediatric Oncology Group of Ontario. Guideline for the prevention and treatment of anticipatory nausea and vomiting due to chemotherapy in pediatric cancer patients. Pediatr Blood Cancer. 2014;61(8):1506-1512. doi: 10.1002/pbc.25063. [PubMed 24753095]
  67. England ML, Ongür D, Konopaske GT, Karmacharya R. Catatonia in psychotic patients: clinical features and treatment response. J Neuropsychiatry Clin Neurosci. 2011;23(2):223-226. [PubMed 21677256]
  68. Food and Drug Administration. General Anesthetic and sedation drugs; drug safety communication - FDA approves label changes for use in young children. Food and Drug Administration website. Accessed July 6, 2017. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-approves-label-changes-use-general-anesthetic-and-sedation-drugs.
  69. Food and Drug Administration. FDA Drug Safety Communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. Food and Drug Administration website. Published December 14, 2016. Updated March 8, 2018. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-review-results-new-warnings-about-using-general-anesthetics-and
  70. Fink M, Taylor MA. The catatonia syndrome: forgotten but not gone. Arch Gen Psychiatry. 2009;66(11):1173-7. doi: 10.1001/archgenpsychiatry.2009.141. [PubMed 19884605]
  71. Fishman DS, Andropoulos DB, Lightdale JR. Sedation and the Food and Drug Administration Warning: What a Pediatric Gastroenterologist, Hepatologist, and Pancreatologist Should Know. J Pediatr Gastroenterol Nutr. 2019;69(1):3-5. doi:10.1097/MPG.0000000000002346 [PubMed 30921252]
  72. Frank C. Recognition and treatment of serotonin syndrome. Can Fam Physician. 2008;54(7):988-992. [PubMed 18625822]
  73. Fraser AA, Ingram IM. Lorazepam dependence and chronic psychosis. Br J Psychiatry. 1985;147:211. [PubMed 4041699]
  74. Furman JM, Barton JJS. Treatment of vertigo. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed September 17, 2021.
  75. Gal P, Reed M. Medications. In: Kliegman RM, Behrman RE, Jenson HB, et al, eds. Nelson Textbook of Pediatrics. 18th ed. Philadelphia, PA: Saunders Elsevier; 2007: 2955-2999.
  76. Giersch A, Boucart M, Elliott M, Vidailhet P. Atypical behavioural effects of lorazepam: clues to the design of novel therapies? Pharmacol Ther. 2010;126(1):94-108. doi:10.1016/j.pharmthera.2010.01.004 [PubMed 20138190]
  77. Glauser T, Shinnar S, Gloss D, et al. Evidence-based guideline: Treatment of convulsive status epilepticus in children and adults: report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48-61. doi: 10.5698/1535-7597-16.1.48 [PubMed 26900382]
  78. Goldney RD. Paradoxical reaction to a new minor tranquilizer. Med J Aust. 1977;1(5):139-40. [PubMed 15198]
  79. Grabowski J, Goldin A, Arthur LG, et al. The effects of early anesthesia on neurodevelopment: A systematic review. J Pediatr Surg. 2021:S0022-3468(21)00014-2. doi:10.1016/j.jpedsurg.2021.01.002 [PubMed 33509654]
  80. Graham MR. Clinical update regarding general anesthesia-associated neurotoxicity in infants and children. Curr Opin Anaesthesiol. 2017;30(6):682-687. doi:10.1097/ACO.0000000000000520 [PubMed 28915132]
  81. Graves NM, Kriel RL, Jones-Saete C. Bioavailability of rectally administered lorazepam. Clin Neuropharmacol. 1987;10(6):555-559. doi: 10.1097/00002826-198712000-00007. [PubMed 3427562]
  82. Greenblatt DJ, Divoll M, Harmatz JS, Shader RI. Pharmacokinetic comparison of sublingual lorazepam with intravenous, intramuscular, and oral lorazepam. J Pharm Sci. 1982;71(2):248-252. doi: 10.1002/jps.2600710227. [PubMed 6121043]
  83. Greenblatt DJ, Shader RI, and Abernethy DR. Drug therapy. Current status of benzodiazepines. N Engl J Med. 1983;309(6):354-358. [PubMed 6135156]
  84. Griffin CE 3rd, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J. 2013;13(2):214-223. [PubMed 23789008]
  85. Guerra GG, Robertson CM, Alton GY, et al; Western Canadian Complex Pediatric Therapies Follow-up Group. Neurodevelopmental outcome following exposure to sedative and analgesic drugs for complex cardiac surgery in infancy. Paediatr Anaesth. 2011;21(9):932-941. doi:10.1111/j.1460-9592.2011.03581.x [PubMed 21507125]
  86. Hain TC, Uddin M. Pharmacological treatment of vertigo. CNS Drugs. 2003;17(2):85-100. doi: 10.2165/00023210-200317020-00002. [PubMed 12521357]
  87. Hanna J, Swetter S. A case of delirium and rhabdomyolysis in severe Iatrogenic opioid withdrawal. Psychosomatics. 2018;59(4):405-407. doi: 10.1016/j.psym.2017.12.002. [PubMed 29325983]
  88. Hansen L, Lange R, Gupta S. Development and evaluation of a guideline for monitoring propylene glycol toxicity in pediatric intensive care unit patients receiving continuous infusion lorazepam. J Pediatr Pharmacol Ther. 2015;20(5):367-372. doi:10.5863/1551-6776-20.5.367 [PubMed 26472950]
  89. Harman SM, Bailey FA. Palliative care: The last hours and days of life. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed December 18, 2020.
  90. Hasan A, Falkai P, Wobrock T, et al; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for Schizophrenia. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry. 2012;13(5):318-378. doi:10.3109/15622975.2012.696143. [PubMed 22834451]
  91. Hasan A, Falkai P, Wobrock T, et al; WFSBP Task Force on Treatment Guidelines for Schizophrenia. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 2: update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects. World J Biol Psychiatry. 2013;14(1):2-44. doi:10.3109/15622975.2012.739708. [PubMed 23216388]
  92. Hegenbarth MA; American Academy of Pediatrics Committee on Drugs. Preparing for pediatric emergencies: drugs to consider. Pediatrics. 2008;121(2):433-443. [PubMed 18245435]
  93. Henry DW, Burwinkle JW, Klutman NE. Determination of sedative and amnestic doses of lorazepam in children. Clin Pharm. 1991;10(8):625-629. [PubMed 1934919]
  94. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO guideline update. J Clin Oncol. 2020;38(24):2782-2797. doi:10.1200/JCO.20.01296 [PubMed 32658626]
  95. Hoffman RS, Weinhouse GL. Management of moderate and severe alcohol withdrawal syndromes. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed October 8, 2019.
  96. Horinek EL, Kiser TH, Fish DN, MacLaren R. Propylene glycol accumulation in critically ill patients receiving continuous intravenous lorazepam infusions. Ann Pharmacother. 2009;43(12):1964-1971. doi:10.1345/aph.1M313 [PubMed 19920159]
  97. Horn E, Nesbit SA. Pharmacology and pharmacokinetics of sedatives and analgesics. Gastrointest Endosc Clin N Am. 2004;14(2):247-268. doi:10.1016/j.giec.2004.01.001 [PubMed 15121142]
  98. Howard P, Twycross R, Shuster J, Mihalyo M, Wilcock A. Benzodiazepines. J Pain Symptom Manage. 2014;47(5):955-964. doi: 10.1016/j.jpainsymman.2014.03.001. [PubMed 24681184]
  99. Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science. 1999;283(5398):70-4. doi:10.1126/science.283.5398.70 [PubMed 9872743]
  100. "Inactive" ingredients in pharmaceutical products: update (subject review). American Academy of Pediatrics (AAP) Committee on Drugs. Pediatrics. 1997;99(2):268-278. [PubMed 9024461]
  101. Iqbal MM, Sobhan T, Ryals T, et al. Effects of Commonly Used Benzodiazepines on the Fetus, the Neonate, and the Nursing Infant. Psychiatr Serv. 2002;53(1):39-49. [PubMed 11773648]
  102. Iqbal O'Meara AM, Miller Ferguson N, Zven SE, et al. Potential neurodevelopmental effects of pediatric intensive care sedation and analgesia: Repetitive benzodiazepine and opioid exposure alters expression of glial and synaptic proteins in juvenile rats. Crit Care Explor. 2020;2(4):e0105. doi:10.1097/CCE.0000000000000105 [PubMed 32426747]
  103. Irwin SA, Hirst JM. Overview of anxiety in palliative care. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 24, 2022.
  104. Ito S. Drug therapy for breast-feeding women. N Engl J Med. 2000;343(2):118-126. [PubMed 10891521]
  105. Jahn A, Bodreau C, Farthing K, Elbarbry F. Assessing propylene glycol toxicity in alcohol withdrawal patients receiving intravenous benzodiazepines: A one-compartment pharmacokinetic model. Eur J Drug Metab Pharmacokinet. 2018;43(4):423-430. doi: 10.1007/s13318-018-0462-1 [PubMed 29392569]
  106. Jennum P, Baandrup L, Ibsen R, et al. Increased all-cause mortality with use of psychotropic medication in dementia patients and controls: A population-based register study. Eur Neuropsychopharmacol. 2015;25(11):1906-1913. doi:10.1016/j.euroneuro.2015.08.014. [PubMed 26342397]
  107. Johnson TJ, Voss G. Continuous infusion of undiluted lorazepam injection. Am J Health Syst Pharm. 2002;59(1):78-79. [PubMed 11813472]
  108. Kalachnik JE, Hanzel TE, Sevenich R, Harder SR. Benzodiazepine behavioral side effects: review and implications for individuals with mental retardation. Am J Ment Retard. 2002;107(5):376-410. doi:10.1352/0895-8017(2002)107<0376:BBSERA>2.0.CO;2 [PubMed 12186578]
  109. Katzman MA, Bleau P, Blier P, Chokka P, Kjernisted K, Van Ameringen M; Canadian Anxiety Guidelines Initiative Group. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14(suppl 1):S1. doi:10.1186/1471-244X-14-S1-S1 [PubMed 25081580]
  110. Kelly LE, Poon S, Madadi P, Koren G. Neonatal benzodiazepines exposure during breastfeeding. J Pediatr. 2012;161(3):448-451. [PubMed 22504099]
  111. Khaldarov N. Benzodiazepines for treatment of neuroleptic malignant syndrome. Hosp Physician. 2000:36(9);51-55.
  112. Kirkby KC, Montgomery IM, Badcock R, Daniels BA. A comparison of age-related deficits in memory and frontal lobe function following oral lorazepam administration. J Psychopharmacol. 1995;9(4):319-25. doi:10.1177/026988119500900405 [PubMed 22298396]
  113. Kliegman RM, Stanton BF, St. Gemell JW, et al, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Saunders Elsevier; 2011.
  114. Kliegman RM and St. Geme J, eds. Nelson Textbook of Pediatrics. 21st ed. Philadelphia, PA: Saunders Elsevier; 2020.
  115. Kraus JW, Desmond PV, Marshall JP, Johnson RF, Schenker S, Wilkinson GR. Effects of aging and liver disease on disposition of lorazepam. Clin Pharmacol Ther. 1978;24(4):411-419. [PubMed 28871]
  116. Lader M. Benzodiazepines revisited--will we ever learn? Addiction. 2011;106(12):2086-2109. doi:10.1111/j.1360-0443.2011.03563.x [PubMed 21714826]
  117. Larsen ER, Damkier P, Pedersen LH, et al. Use of psychotropic drugs during pregnancy and breast-feeding. Acta Psychiatr Scand Suppl. 2015;(445):1-28. [PubMed 26344706]
  118. Lavonas EJ. First-generation (typical) antipsychotic medication poisoning. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed May 21, 2021.
  119. Lemmer P, Schneider S, Mühe A, Wennig R. Quantification of lorazepam and lormetazepam in human breast milk using GC-MS in the negative chemical ionization mode. J Anal Toxicol. 2007;31(4):224-226. [PubMed 17555647]
  120. Leppik IE, Patel SI. Intramuscular and rectal therapies of acute seizures. Epilepsy Behav. 2015;49:307-312. doi: 10.1016/j.yebeh.2015.05.001. [PubMed 26071998]
  121. Levin TT, Cortes-Ladino A, Weiss M, Palomba ML. Life-threatening serotonin toxicity due to a citalopram-fluconazole drug interaction: case reports and discussion. Gen Hosp Psychiatry. 2008;30(4):372-377. doi: 10.1016/j.genhosppsych.2008.03.008. [PubMed 18585543]
  122. Lim TY, Poole RL, Pageler NM. Propylene glycol toxicity in children. J Pediatr Pharmacol Ther. 2014;19(4):277-282. doi:10.5863/1551-6776-19.4.277 [PubMed 25762872]
  123. Little JD, Taghavi EH. Disinhibition after lorazepam augmentation of antipsychotic medication. Am J Psychiatry. 1991;148(8):1099-100. doi:10.1176/ajp.148.8.1099a [PubMed 1677237]
  124. Lohr L. Chemotherapy-induced nausea and vomiting. Cancer J. 2008;14(2):85-93. [PubMed 18391612]
  125. Lonardo NW, Mone MC, Nirula R, et al. Propofol is associated with favorable outcomes compared with benzodiazepines in ventilated intensive care unit patients [published correction appears in Am J Respir Crit Care Med. 2014;189(11):e70]. Am J Respir Crit Care Med. 2014;189(11):1383-1394. doi: 10.1164/rccm.201312-2291OC. [PubMed 24720509]
  126. Lorazepam injection [prescribing information]. Eatontown, NJ: West-ward Pharmaceuticals; June 2011.
  127. Lorazepam injection USP solution 2 mg/mL (lorazepam) [product monograph]. Boucherville, Quebec, Canada: Sandoz Canada Inc; May 2021.
  128. Lorazepam injection USP sterile solution 4 mg/mL (lorazepam) [product monograph]. Kirkland, Quebec, Canada: Pfizer Canada ULC; August 2019.
  129. Lorazepam oral concentrate [prescribing information]. Branchburg, NJ: Amneal Pharmaceuticals LLC; March 2021.
  130. Lorazepam tablets [prescribing information]. Columbus, OH: American Health Packaging.
  131. Loreev XR capsules [prescribing information]. Morristown, NJ: Almatica Pharma LLC; August 2021.
  132. Lucca JM, Ramesh M, Parthasarathi G, Ram D. Lorazepam-induced diplopia. Indian J Pharmacol. 2014;46(2):228-229. doi:10.4103/0253-7613.129328 [PubMed 24741200]
  133. Malcolm R, Myrick H, Roberts J, Wang W, Anton RF, Ballenger JC. The effects of carbamazepine and lorazepam on single versus multiple previous alcohol withdrawals in an outpatient randomized trial. J Gen Intern Med. 2002;17(5):349-355. [PubMed 12047731]
  134. Male CG, Johnson HD. Oral benzodiazepine premedication in minor gynaecological surgery. Br J Anaesth. 1984;56(5):499-507. doi:10.1093/bja/56.5.499. [PubMed 6144317]
  135. Mancuso CE, Tanzi MG, Gabay M. Paradoxical reactions to benzodiazepines: literature review and treatment options. Pharmacotherapy. 2004;24(9):1177-1185. [PubMed 15460178]
  136. Marill KA, Walsh MJ, Nelson BK. Intravenous lorazepam versus dimenhydrinate for treatment of vertigo in the emergency department: a randomized clinical trial. Ann Emerg Med. 2000;36(4):310-319. doi: 10.1067/mem.2000.110580. [PubMed 11020677]
  137. Maytal J, Novak GP, King KC. Lorazepam in the treatment of refractory neonatal seizures. J Child Neurol. 1991;6(4):319-323. [PubMed 1940133]
  138. McDermott CA, Kowalczyk AL, Schnitzler ER, et al. Pharmacokinetics of Lorazepam in Critically Ill Neonates With Seizures. J Pediatr. 1992;120(3):479-483. [PubMed 1538303]
  139. McKee HR, Abou-Khalil B. Outpatient pharmacotherapy and modes of administration for acute repetitive and prolonged seizures. CNS Drugs. 2015;29(1):55-70. doi:10.1007/s40263-014-0219-6. [PubMed 25583219]
  140. McPherson C. Sedation and analgesia in mechanically ventilated preterm neonates: continue standard of care or experiment? J Pediatr Pharmacol Ther. 2012;17(4):351-364. doi:10.5863/1551-6776-17.4.351 [PubMed 23413121]
  141. Mejo SL. Anterograde amnesia linked to benzodiazepines. Nurse Pract. 1992;17(10):44, 49-50. doi:10.1097/00006205-199210000-00013 [PubMed 1357612]
  142. Moore G, Pfaff, JA. Assessment and emergency management of the acutely agitated or violent adult. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed February 6, 2020.
  143. Morrison G, Chiang ST, Koepke HH, Walker BR. Effect of renal impairment and hemodialysis on lorazepam kinetics. Clin Pharmacol Ther. 1984;35(5):646-652. doi:10.1038/clpt.1984.89 [PubMed 6713774]
  144. Mundeleer P. Child premedication per os with lorazepam. Acta Anaesthesiol Belg. 1980;(31)(suppl):187-193. [PubMed 6109421]
  145. Myrick H, Malcolm R, Randall PK, et al. A double-blind trial of gabapentin versus lorazepam in the treatment of alcohol withdrawal. Alcohol Clin Exp Res. 2009;33(9):1582-1588. doi:10.1111/j.1530-0277.2009.00986.x. [PubMed 19485969]
  146. National Institute for Health and Care Excellence (NICE). Epilepsies: diagnosis and management. https://www.nice.org.uk/guidance/cg137/resources/epilepsies-diagnosis-and-management-35109515407813 Published January 2012.
  147. Neale BW, Mesler EL, Young M, Rebuck JA, Weise WJ. Propylene glycol-induced lactic acidosis in a patient with normal renal function: a proposed mechanism and monitoring recommendations. Ann Pharmacother. 2005;39(10):1732-1736. doi:10.1345/aph.1G083 [PubMed 16159998]
  148. Nelsen JL, Haas CE, Habtemariam B, et al. A prospective evaluation of propylene glycol clearance and accumulation during continuous-infusion lorazepam in critically ill patients. J Intensive Care Med. 2008;23(3):184-194. doi:10.1177/0885066608315808 [PubMed 18543419]
  149. Nelson J, Chouinard G; Canadian Society for Clinical Pharmacology. Guidelines for the clinical use of benzodiazepines: pharmacokinetics, dependency, rebound and withdrawal. Can J Clin Pharmacol. 1999;6(2):69-83. [PubMed 10519733]
  150. Nelson L, Odujebe O. Cocaine: Acute intoxication. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 24, 2022.
  151. O'Boyle CA. Benzodiazepine-induced amnesia and anaesthetic practice: a review. Psychopharmacol Ser. 1988;6:146-65. [PubMed 2905804]
  152. O'Connor FG, Casa DJ. Exertional heat illness in adolescents and adults: Management and prevention. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed May 5, 2020.
  153. Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007;298(22):2644-2653. [PubMed 18073360]
  154. Pandit SK, Heisterkamp DV, Cohen PJ. Further studies of the anti-recall effect of lorazepam: A dose--time--effect relationship. Anesthesiology. 1976;45(5):495-500. [PubMed 9845]
  155. Park TW. Benzodiazepine use disorder. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed March 16, 2021.
  156. Peppers MP. Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease. Pharmacotherapy. 1996;16(1):49-57. [PubMed 8700792]
  157. Peters CG, Brunton JT. Comparative study of lorazepam and trimeprazine for oral premedication in paediatric anaesthesia. Br J Anaesth. 1982;54(6):623-628. [PubMed 6123337]
  158. Pietras CJ, Lieving LM, Cherek DR, Lane SD, Tcheremissine OV, Nouvion S. Acute effects of lorazepam on laboratory measures of aggressive and escape responses of adult male parolees. Behav Pharmacol. 2005;16(4):243-51. doi:10.1097/01.fbp.0000170910.53415.77 [PubMed 15961964]
  159. Reddy MSS, Achary U, Harbishettar V, Sivakumar PT, Varghese M. Paradoxical reaction to benzodiazepines in elderly - Case series. Asian J Psychiatr. 2018;35:8-10. doi:10.1016/j.ajp.2018.04.037 [PubMed 29723722]
  160. Richardson JK, Eckner JT, Kim H, Ashton-Miller JA. A clinical method of evaluating simple reaction time and reaction accuracy is sensitive to a single dose of lorazepam. J Psychopharmacol. 2020;34(8):920-925. doi:10.1177/0269881120915409 [PubMed 32536331]
  161. Rosebush PI, Mazurek MF. Catatonia and its treatment. Schizophr Bull. 2010;36(2):239-242. [PubMed 19969591]
  162. Roy-Byrne PP. Management of psychiatric disorders in patients with cancer. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed November 2, 2021.
  163. Rozendaal FW, Spronk PE, Snellen FF, et al; UltiSAFE investigators. Remifentanil-propofol analgo-sedation shortens duration of ventilation and length of ICU stay compared to a conventional regimen: a centre randomised, cross-over, open-label study in the Netherlands. Intensive Care Med. 2009;35(2):291-298. doi: 10.1007/s00134-008-1328-9. [PubMed 18949456]
  164. Saarelainen L, Tolppanen AM, Koponen M, et al. Risk of death associated with new benzodiazepine use among persons with Alzheimer disease: A matched cohort study. Int J Geriatr Psychiatry. 2018;33(4):583-590. doi: 10.1002/gps.4821. [PubMed 29143367]
  165. Sachdeva A, Chandra M, Deshpande SN. A comparative study of fixed tapering dose regimen versus symptom-triggered regimen of lorazepam for alcohol detoxification. Alcohol Alcohol. 2014;49(3):287-291. doi: 10.1093/alcalc/agt181. [PubMed 24407777]
  166. Schachter SC. Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed December 8, 2020.
  167. Scharf MB, Kales A, Bixler EO, Jacoby JA, Schweitzer PK. Lorazepam-efficacy, side effects, and rebound phenomena. Clin Pharmacol Ther. 1982;31(2):175-179. doi:10.1038/clpt.1982.27 [PubMed 6120058]
  168. Shader RI, Dreyfuss D, Gerrein JR, Harmatz JS, Allison SJ, Greenblatt DJ. Sedative effects and impaired learning and recall after single oral doses of lorazepam. Clin Pharmacol Ther. 1986;39(5):526-529. doi:10.1038/clpt.1986.90 [PubMed 3698460]
  169. Shehab N, Lewis CL, Streetman DD, Donn SM. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. Pediatr Crit Care Med. 2009;10(2):256-259. [PubMed 19188870]
  170. Shih G, Wallace R. First-trimester pregnancy termination: Uterine aspiration. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed December 8, 2020.
  171. Short TG, Forrest P, Galletly DC. Paradoxical reactions to benzodiazepines--a genetically determined phenomenon? Anaesth Intensive Care. 1987;15(3):330-331. doi:10.1177/0310057X8701500314 [PubMed 3661967]
  172. Society for Pediatric Sedation (SPS). FDA advisory on anesthesia and sedation medication in children. Society for Pediatric Sedation website. Accessed April 2021. https://www.pedsedation.org/resources/quality-safety/fda-advisory/#:~:text=In%20December%202016%2C%20the%20FDA,(http%3A%2F%2Fwww.fda.
  173. Soyka M, Kranzler HR, Hesselbrock V, Kasper S, Mutschler J, Möller HJ; WFSBP Task Force on Treatment Guidelines for Substance Use Disorders. Guidelines for biological treatment of substance use and related disorders, part 1: Alcoholism, first revision. World J Biol Psychiatry. 2017;18(2):86-119. doi: 10.1080/15622975.2016.1246752. [PubMed 28006997]
  174. Stein MB. Pharmacotherapy for social anxiety disorder in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed April 29, 2019.
  175. Stewart SA. The effects of benzodiazepines on cognition. J Clin Psychiatry. 2005;66(suppl 2):9-13. [PubMed 15762814]
  176. Stolbach A, Hoffman RS. Opioid withdrawal in the emergency setting. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed May 8, 2019.
  177. Stroup TS. Schizophrenia in adults: Maintenance therapy and side effect management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed October 5, 2021.
  178. Swart EL, de Jongh J, Zuideveld KP, Danhof M, Thijs LG, Strack van Schijndel RJ. Population pharmacokinetics of lorazepam and midazolam and their metabolites in intensive care patients on continuous venovenous hemofiltration. Am J Kidney Dis. 2005;45(2):360-371. doi:10.1053/j.ajkd.2004.09.004 [PubMed 15685515]
  179. Swartz R, Longwell P. Treatment of vertigo. Am Fam Physician. 2005;71(6):1115-1122. [PubMed 15791890]
  180. Swinson R, McCabe RE. Pharmacotherapy for specific phobia in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed April 29, 2019.
  181. Tietze KJ, Fuchs B. Sedative-analgesic medications in critically ill adults: Properties, dosage regimens, and adverse effects. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 11, 2022.
  182. Tormoehlen LM, Rusyniak DE. Neuroleptic malignant syndrome and serotonin syndrome. Handb Clin Neurol. 2018;157:663-675. doi: 10.1016/B978-0-444-64074-1.00039-2. [PubMed 30459031]
  183. Tsai MC, Huang TL. Severe neuroleptic malignant syndrome: successful treatment with high-dose lorazepam and diazepam: a case report. Chang Gung Med J. 2010;33(5):576-580. [PubMed 20979709]
  184. Tsuda M, Shimizu N, Suzuki T. Contribution of glutamate receptors to benzodiazepine withdrawal signs. Jpn J Pharmacol. 1999;81(1):1-6. doi:10.1254/jjp.81.1 [PubMed 10580363]
  185. Turkington D, Gill P. Mania induced by lorazepam withdrawal: a report of two cases. J Affect Disord. 1989;17(1):93-95. doi:10.1016/0165-0327(89)90028-1 [PubMed 2525581]
  186. US Department of Veterans Affairs/Department of Defense (VA/DoD). VA/DoD clinical practice guideline for the management of posttraumatic stress disorder and acute stress reaction. https://www.healthquality.va.gov/guidelines/mh/ptsd/. Updated 2017. Accessed September 8, 2021.
  187. US Department of Veterans Affairs/Department of Defense (VA/DoD). VA/DoD clinical practice guideline for the management of substance use disorders. https://www.healthquality.va.gov/guidelines/MH/sud/VADODSUDCPGRevised22216.pdf. Published December 2015. Accessed March 16, 2021.
  188. van Laar M, Volkerts E, Verbaten M. Subchronic effects of the GABA-agonist lorazepam and the 5-HT2A/2C antagonist ritanserin on driving performance, slow wave sleep and daytime sleepiness in healthy volunteers. Psychopharmacology (Berl). 2001;154(2):189-197. doi:10.1007/s002130000633 [PubMed 11314681]
  189. Verbeeck R, Tjandramaga TB, Verberckmoes R, De Schepper PJ. Biotransformation and excretion of lorazepam in patients with chronic renal failure. Br J Clin Pharmacol. 1976;3(6):1033-1039. doi:10.1111/j.1365-2125.1976.tb00354.x [PubMed 22216526]
  190. Vinkers CH, Olivier B. Mechanisms underlying tolerance after long-term benzodiazepine use: a future for subtype-selective gaba(a) receptor modulators? Adv Pharmacol Sci. 2012;2012:1-19. [PubMed 22536226]
  191. Wang RZ, Vashistha V, Kaur S, Houchens NW. Serotonin syndrome: Preventing, recognizing, and treating it. Cleve Clin J Med. 2016;83(11):810-817. doi:10.3949/ccjm.83a.15129 [PubMed 27824534]
  192. Ware MR, Feller DB, Hall KL. Neuroleptic malignant syndrome: diagnosis and management. Prim Care Companion CNS Disord. 2018;20(1). pii: 17r02185. doi:10.4088/PCC.17r02185 [PubMed 29325237]
  193. Whitelaw AG, Cummings AJ, McFadyen IR. Effect of maternal lorazepam on the neonate. Br Med J (Clin Res Ed). 1981;282(6270):1106-1108. [PubMed 6113019]
  194. Wightman RS, Nelson LS, Lee JD, Fox LM, Smith SW. Severe opioid withdrawal precipitated by Vivitrol. Am J Emerg Med. 2018;36(6):1128.e1-1128.e2. doi:10.1016/j.ajem.2018.03.052 [PubMed 29605483]
  195. Wijdicks EFM. Neuroleptic malignant syndrome. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed April 30, 2019.
  196. Wikner BN, Stiller CO, Bergman U, et al. Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: neonatal outcome and congenital malformations. Pharmacoepidemiol Drug Saf. 2007;16(11):1203-1210. [PubMed 17894421]
  197. Wilson KC, Reardon C, Farber HW. Propylene glycol toxicity in a patient receiving intravenous diazepam. N Engl J Med. 2000;343(11):815. doi:10.1056/nejm200009143431115 [PubMed 10991709]
  198. Wilson S, Anderson K, Baldwin D, et al. British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders: an update. J Psychopharmacol. 2019;33(8):923-947. doi:10.1177/0269881119855343 [PubMed 31271339]
  199. Wodarz N, Krampe-Scheidler A, Christ M, et al. Evidence-based guidelines for the pharmacological management of acute methamphetamine-related disorders and toxicity. Pharmacopsychiatry. 2017;50(3):87-95. doi: 10.1055/s-0042-123752. [PubMed 28297728]
  200. World Health Organization (WHO). Breastfeeding and maternal medication, recommendations for drugs in the Eleventh WHO Model List of Essential Drugs. 2002. Available at http://www.who.int/maternal_child_adolescent/documents/55732/en/
  201. Vinkers CH, Olivier B. Mechanisms underlying tolerance after long-term benzodiazepine use: A future for subtype-selective GABA(A) receptor modulators? Adv Pharmacol Sci. 2012;2012:416864. doi:10.1155/2012/416864 [PubMed 22536226]
  202. von Gunten C, Buckholz G. Palliative care: Overview of cough, stridor, and hemoptysis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed April 29, 2019.
  203. Yahwak JA, Riker RR, Fraser GL, Subak-Sharpe S. Determination of a lorazepam dose threshold for using the osmol gap to monitor for propylene glycol toxicity. Pharmacotherapy. 2008;28(8):984-991. [PubMed 18657015]
  204. Yaucher NE, Fish JT, Smith HW, Wells JA. Propylene glycol-associated renal toxicity from lorazepam infusion. Pharmacotherapy. 2003;23(9):1094-1099. doi:10.1592/phco.23.10.1094.32762 [PubMed 14524641]
  205. Ziegenbein M, Kropp S. Lorazepam-induced prolongation of the QT interval in a patient with schizoaffective disorder and complete AV block. Can J Psychiatry. 2004;49(6):414. doi:10.1177/070674370404900619 [PubMed 15283543]
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