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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
  • Antiseizure Agent, Benzodiazepine;
  • Benzodiazepine
Dosing: Adult

Note: Reduce dose or avoid use in patients receiving opioids or with significant chronic disease (eg, respiratory compromise). Avoid use in patients with a history of substance use, misuse of medications, or depression, except for acute or emergency situations (eg, acute agitation, status epilepticus) (Ref).

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 (Ref).

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 (Ref).

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 (eg, 0.5 mg/day) therapy may be considered in select patients, when preferred treatments are ineffective or poorly tolerated (Ref). Use with caution in patients with comorbid posttraumatic stress disorder (PTSD); benzodiazepines may worsen PTSD symptoms (Ref).

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 (Ref).

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 (Ref). 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 (Ref).

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 (Ref).

Oral (immediate release): 0.5 to 2 mg once 30 to 60 minutes before the stimulus (Ref).

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 (Ref).

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 (Ref).

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 (Ref).

IV (preferred): 1 to 2 mg once; if no response in 5 to 10 minutes, repeat dose once (Ref).

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

Treatment: Note: For patients with malignant catatonia, electroconvulsive therapy should begin immediately (Ref).

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 (Ref). For patients at risk of cardiorespiratory compromise or oversedation, some experts recommend initiating with 0.5 mg 3 times daily (Ref).

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 (Ref).

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 (Ref).

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 (Ref). 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 (Ref).

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 (Ref). 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 (Ref).

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 (Ref).

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) (Ref).

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) (Ref).

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome (adjunctive therapy) (off-label use):

Note: Following withdrawal of causative agent while continuing supportive care, use for moderate to severe muscle rigidity with elevated creatine kinase. May also use for any patient experiencing agitation (Ref).

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 (Ref).

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 (Ref).

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 (Ref).

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 (Ref).

Serotonin syndrome

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

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 (Ref).

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) (Ref).

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) (Ref).

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 (Ref).

Vertigo, acute episodes

Vertigo, acute episodes (alternative agent) (off-label use):

Note: Reserve use for symptomatic relief of episodes lasting several hours to days (maximum duration: 3 days); chronic use may impede adaptation and recovery (Ref).

IM, IV, Oral (immediate release): 0.5 to 2 mg every 4 to 12 hours as needed for up to 48 to 72 hours (Ref).

Discontinuation of therapy: Unless safety concerns require a more rapid withdrawal, gradually taper to detect reemerging symptoms and minimize rebound and withdrawal symptoms in patients receiving therapy ≥4 weeks or as appropriate based on patient-specific factors (Ref).

Low or moderate dose, no concerns for benzodiazepine use disorder: Taper total daily dose by 20% to 25% every week based on response and tolerability (taper increments will be limited by available dosage forms) (Ref).

Extended or high-dose therapy, or suspected benzodiazepine use disorder: Taper total daily dose by approximately 25% every 1 to 2 weeks based on response, tolerability, and individual patient factors (taper increments will be limited by available dosage forms) (Ref). Reduce dose more rapidly in the beginning, and slow the dose reduction as the taper progresses because earlier stages of withdrawal are easier to tolerate (Ref). The optimal duration and taper increment will vary; up to 6 months may be necessary for some patients on higher doses, and a taper rate of 50% every week may be tolerated in some patients (Ref). 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 (Ref).

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 A 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 (Ref).

Parenteral: No dosage adjustment necessary for acute doses (Ref); 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 (Ref).

Hemodialysis, intermittent (thrice weekly): Not significantly dialyzed (Ref): 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 (Ref).

Peritoneal dialysis: Unlikely to be dialyzed (highly protein bound): Oral, Parenteral: No dosage adjustment necessary (Ref); 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 (Ref).

CRRT: Not significantly dialyzed (Ref): Oral, Parenteral: No dosage adjustment necessary (Ref); 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 (Ref).

PIRRT (eg, sustained, low-efficiency diafiltration): Unlikely to be dialyzed (highly protein bound): Oral, Parenteral: No dosage adjustment necessary (Ref); 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 (Ref).

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 (Ref).

Dosing: Pediatric

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

Chemotherapy-induced nausea and vomiting, anticipatory

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 (Ref).

Chemotherapy-associated nausea and vomiting, breakthrough

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 (Ref).

Anxiety, acute

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 (Ref).

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

Sedation

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 (Ref). Note: In adults, the maximum dose is 4 mg/dose.

Status epilepticus

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 (Ref).

Intranasal: Note: Lorazepam is not the preferred agent for intranasal administration, guidelines recommend midazolam as the preferred agent (Ref).

Infants, Children, and Adolescents: 0.1 mg/kg/dose; maximum dose: 5 mg/dose (Ref).

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 (Ref).

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 (Ref).

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).

Dosing: Obesity: Adult

The recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.

Class 1, 2, and 3 obesity (BMI ≥30 kg/m2):

Intermittent:

IV, IM: Use of non–weight-based dosing is preferred; titrate to clinical effect if needed (Ref). If weight-based doses are utilized, use adjusted body weight for initial dose calculations, then titrate to clinical effect if needed (Ref). If rapid sedation or clinical effect is needed, use actual body weight for initial weight-based dose calculations, then titrate to clinical effect (Ref). Clinicians should not change dosing weight from one weight metric to another during therapy (ie, actual body weight to/from adjusted body weight) (Ref). Refer to adult dosing for indication-specific doses.

Oral, Sublingual: Use non–weight-based dosing; titrate to clinical effect if needed (Ref). Refer to adult dosing for indication-specific doses (Ref).

Continuous infusion: Note: Intermittent dosing is preferred for the ICU patient. Use continuous infusion only when ICU patient requiring sedation is refractory to intermittent therapy (Ref). Lorazepam continuous infusions are not recommended for use in most ICU patients due to drug accumulation, oversedation, propylene glycol (PG) accumulation, and subsequent complications (osmol gap metabolic acidosis, kidney failure); nonbenzodiazepine or midazolam continuous infusions are generally preferred (Ref). If lorazepam continuous infusion is used, monitor for PG accumulation with osmol gap (Ref).

IV: Use of non–weight-based dosing is preferred; titrate to clinical effect (Ref). If weight-based doses are utilized, use adjusted body weight for initial dose calculations, then titrate to clinical effect (Ref). Clinicians should not change dosing weight from one weight metric to another during therapy (ie, actual body weight to/from adjusted body weight) (Ref). Refer to adult dosing for indication-specific dosing.

Rationale for recommendations:

There are limited data on the effects of obesity on lorazepam dosing or pharmacokinetics. One lorazepam pharmacokinetic study in subjects with obesity demonstrated both an increased Vd and clearance, but no difference in half-life compared to subjects who were not obese (Ref). Due to the increased Vd, these pharmacokinetic data suggest larger doses may be required. However, larger doses may increase adverse drug effects, particularly in select populations (eg, elderly or nonintubated patients). In general, smaller doses that can be rapidly titrated to effect are preferred (Ref).

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, fd&c yellow #5 (tartrazine)]

Loreev XR: 1.5 mg [contains corn starch, fd&c blue #1 (brilliant blue)]

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

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

Concentrate, Oral:

LORazepam Intensol: 2 mg/mL (30 mL) [alcohol free, dye free, sugar free; contains polyethylene glycol (macrogol), 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 (macrogol), 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. [DSC] = Discontinued product

Solution, Injection:

Generic: 2 mg/mL ([DSC]); 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 (brill blue) aluminum lake, fd&c yellow #6(sunset yellow)alumin lake, quinoline (d&c yellow #10) aluminum lake]

Ativan: 1 mg

Ativan: 2 mg [contains fd&c blue #2 (indigo carm) 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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/017794s048lbl.pdf#page=13

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) (Ref).

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

Sublingual:

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

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

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 (Ref).

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

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.

Older Adult: 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 short-term anterograde amnesia (ie, memory of information or events after drug administration). Retrograde amnesia (ie, events or information prior to drug administration) is unaffected. However, the magnitude of the amnesic effect from benzodiazepines differs among the various agents, depending on their pharmacokinetic/pharmacodynamic properties, route of administration, and dose. Anterograde amnesia is associated with higher doses, IV administration, and benzodiazepines with faster absorption and higher potency. (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. 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 is composed of five subunits, each with multiple isoforms. Each receptor complex contains a benzodiazepine-binding site, which is classified into several types, based on the alpha subunit isoforms and clinical effects related to each type. The BZ1 receptor type, containing the alfa1 subunit isoform, is highly concentrated in the cortex, thalamus, and cerebellum, and 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).

• Higher doses (Ref)

CNS effects

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 (particularly in older adults) (Ref). Tolerance usually develops to the sedative effects (Ref).

Mechanism: Dose-related (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. Benzodiazepine-associated sedation are mediated by the alpha 1-containing GABA-A receptors (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 or behavioral disinhibition, 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 serotonergic neurotransmission, subsequently causing aggressive behavior. Another mechanism is that in select patients with genetic variations in GABA-A receptors, 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:

Benzodiazepines, in general:

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)

Other potential risk factors: 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:

- Neonates: Large amounts of propylene glycol orally, IV (eg, >3,000 mg/day), or topically (Ref)

- Adult: 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)

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. Benzodiazepine-associated 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). 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. However, in general, 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. (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)-, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-receptors, and metabotropic glutamate (mGlu) receptors, has also been suggested. In mice and rat studies, antagonists for glutamate receptors 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 (eg, benzodiazepines) have an onset ranging from 24 hours to 6 weeks following a decrease, discontinuation, or switch (Ref).

Risk factors:

Benzodiazepines, in general:

• 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).

• Long treatment durations (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 and 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 agents (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: Avoid use in patients with depression because of concerns about worsening mood symptoms, particularly if suicidal risk may be present, except for acute or emergency situations (eg, acute agitation, status epilepticus) (Craske 2022).

• 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: Reduce dose or avoid use 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.

• Older adult patients: Older adult patients may be at an increased risk of death with use; risk has been found highest within the first 4 months of use in older adult 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

Use with caution in neonates, especially in preterm infants; several cases of neurotoxicity and myoclonus (rhythmic myoclonic jerking) have been reported.

Some dosage forms may contain propylene glycol.

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Alcohol (Ethyl): May enhance the CNS depressant effect of LORazepam. Alcohol (Ethyl) may increase the serum concentration of LORazepam. Specifically, this increase in concentration would only occur with use of lorazepam extended release capsules and alcohol. 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. Monitor for respiratory depression, hypotension, and other toxicities if these agents are combined. 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

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. 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

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

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. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification

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

Ornidazole: May enhance the adverse/toxic effect of Products Containing Propylene Glycol. Specifically, a disulfiram-like reaction may occur. Risk X: Avoid combination

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

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

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): $17.00

1.5 mg (per each): $17.00

2 mg (per each): $17.00

3 mg (per each): $17.00

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): $0.90 - $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): $0.10 - $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);
  • 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);
  • 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 code abbreviations (show table)
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