Version October 2023
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.
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.
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.
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 (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 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 (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 (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: 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 (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 (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: 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 toxicity) (off-label use): IV: 2 to 4 mg IV every 8 to 10 minutes based upon patient response (Ref).
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 (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.
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).
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).
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).
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).
(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 (Ref).
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).
Sedation; procedural: 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: 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.
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).
Children ≥12 years and Adolescents: No dosage adjustment necessary. For severe hepatic disease, use with caution; benzodiazepines may worsen hepatic encephalopathy.
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)
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)
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, 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, 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)
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)
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)
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.
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.
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.
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
May be product dependent
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): $1.27 - $4.31
4 mg/mL (per mL): $2.16 - $3.40
Tablets (Ativan Oral)
0.5 mg (per each): $39.87
1 mg (per each): $53.26
2 mg (per each): $84.87
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.
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
C-IV
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.
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
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/2023/017794s049lbl.pdf#page=14
Loreev XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/214826s003lbl.pdf#page=16
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.
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
LORazepam may be confused with ALPRAZolam, clonazePAM, diazePAM, KlonoPIN, Lovaza, temazepam, zolpidem.
Ativan may be confused with Ambien, Atarax, Atgam, Avitene.
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.
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]). Note: Updates for the American Geriatrics Society 2023 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults are in process.
Injection dosage form contains propylene glycol. Monitor for toxicity when administering continuous or high-dose lorazepam infusions.
None known.
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
Ilaprazole: May increase the serum concentration of Benzodiazepines. Risk C: Monitor therapy
Ixabepilone: 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
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
Evaluate pregnancy status prior to use. Pregnancy testing is recommended before treating acute alcohol withdrawal symptoms (ASAM 2020).
Therapy for anxiety should be individualized (BAP [McAllister-Williams 2017]); avoid the use of benzodiazepines for the treatment of anxiety disorders in patients planning to become pregnant (Larsen 2015).
Lorazepam and its metabolite cross the human placenta (Kanto 1982; Papini 2006).
In utero exposure to benzodiazepines has the potential to cause harm to the fetus. Teratogenic effects have been observed in some studies; however, a clear association has not been reported and additional data are needed (Bellantuono 2013; Freeman 2018; Grigoriadis 2019; Noh 2022; Szpunar 2022; Tinker 2019; Wikner 2007). Exposure to a benzodiazepine late in pregnancy may cause neonatal sedation (hypotonia, lethargy, respiratory depression) and/or symptoms of neonatal withdrawal (feeding difficulties, hyperreflexia, inconsolable crying, irritability, restlessness, tremors). Data related to long-term effects on neurodevelopment are inconclusive (Chen 2022; Radojčić 2017; Sundbakk 2022; Wang 2022). Newborns exposed to lorazepam in utero should be monitored for feeding problems, respiratory depression, sedation, and withdrawal.
Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of lorazepam may be altered, resulting in an increased apparent Vd, increased apparent oral clearance, and decreased elimination half-life (Papini 2006). Elimination of lorazepam in the newborn infant is slow; following in utero exposure, term infants may excrete lorazepam for up to 8 days (Whitelaw 1981).
Treatment for alcohol withdrawal may be considered for pregnant patients with at least moderate symptoms (CIWA-Ar scores ≥10) (ASAM 2020). The short-term use of a long-acting benzodiazepine may be used in pregnant patients requiring treatment of acute alcohol withdrawal symptoms (WHO 2014); however, the use of shorter-acting benzodiazepines is preferred in patients at risk for preterm delivery or when treatment is needed during the third trimester (ASAM 2020). Although recommendations vary by guideline, the use of a benzodiazepine other than lorazepam may be preferred during pregnancy (BAP [McAllister-Williams 2017]; SOGC [Graves 2020]; WFSBP/IAWMH [Thibaut 2019]). Monitor newborns for fetal alcohol spectrum disorders in addition to benzodiazepine intoxication (ASAM 2020).
Therapy for anxiety during pregnancy should be individualized. Untreated or inadequately treated psychiatric illness may lead to poor adherence to prenatal care and adverse pregnancy outcomes (ACOG 2008). Benzodiazepines are not preferred when pharmacologic treatment for anxiety disorders is needed during pregnancy, (BAP [McAllister-Williams 2017]; Larsen 2015) and when a benzodiazepine is needed, the use of lorazepam is not preferred. If possible, avoid scheduled doses of benzodiazepines in the month prior to delivery to reduce the risk of withdrawal symptoms in the newborn (Larsen 2015).
Data collection to monitor pregnancy and infant outcomes following exposure to lorazepam is ongoing. Health care providers are encouraged to enroll patients exposed to lorazepam during pregnancy in the National Pregnancy Registry for Psychiatric Medications (866-961-2388).
Lorazepam is present in breast milk.
Data related to the presence of lorazepam in breast milk are available:
Following maternal administration of oral lorazepam 2.5 mg twice daily for the first 5 days postpartum, breast milk concentrations of lorazepam and lorazepam glucuronide were 12 ng/mL and 35 ng/mL, respectively. Authors of the study calculated the estimated exposure of lorazepam to this breastfeeding infant to be 2.6 mcg/kg/day (based on a milk intake of 200 mL/kg/day). The authors of the study also calculated the estimated exposure of lorazepam + lorazepam glucuronide via breast milk to be 9.6 mcg/kg/day. Adverse events were not observed in the neonate (Whitelaw 1981).
Breast milk from 4 lactating patients was collected following a single dose of lorazepam 3.5 mg given orally prior to postpartum sterilization. Four hours after the dose, concentrations of lorazepam in breast milk were 8 to 9 ng/mL (Summerfield 1985).
Breast milk was collected from 3 patients, 3 to 6 days postpartum, who had been taking lorazepam 0.5 mg/day during pregnancy and after delivery. Breast milk was sampled 2 hours after the maternal dose, approximately when the peak maternal plasma concentration occurs. Additional breast milk samples were collected at random times during the 1-month check-up. Peak lorazepam concentrations in breast milk ranged from 1.64 to 1.98 ng/mL when sampled postpartum. The authors of the study calculated the relative infant dose (RID) of lorazepam via breast milk, compared to the weight-adjusted maternal dose, 2 different ways - first by using the actual amount of breast milk ingested, then by using a theoretical milk intake of 150 mL/kg/day (the average amount ingested by an exclusively breastfed infant). The RID of lorazepam for these patients was calculated to be 1% to 1.5% (based on the actual amount of breast milk ingested) and 2.1% to 4.4% (based on theoretical breast milk intake). When breast milk was sampled at the 1-month visit, the RID for lorazepam ranged from 0.7% to 1.9% (based on actual intake) and 1.7% to 2.7% (based on theoretical value) (Nishimura 2021).
Higher breast milk concentrations were observed in 1 mother who received both oral lorazepam and lormetazepam, which is partially metabolized to lorazepam (Lemmer 2007).
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).
Drowsiness, lethargy, or weight loss in breastfeeding infants have been observed in case reports following maternal use of some benzodiazepines (Iqbal 2002). Adverse events following benzodiazepine exposure via breast milk were evaluated in a study of 124 infants (2 to 24 months of age). Lorazepam use was reported by 54% of their mothers. CNS depression was observed in 2 breastfed infants, neither exposed to lorazepam (Kelly 2012).
Breastfeeding during benzodiazepine therapy is not recommended due to the potential for drowsiness in the breastfeeding infant (Larsen 2015). If a benzodiazepine is needed in breastfeeding patients, the use of a short-acting agent is preferred, and infants should be monitored. A single maternal dose of lorazepam may be compatible with breastfeeding (WHO 2002).
Breastfeeding is not recommended when pharmacologic treatment is needed for the management of acute alcohol withdrawal symptoms (WFSBP/IAWMH [Thibaut 2019]).
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]).
Short-to-intermediate-acting benzodiazepine (based on half-life) (Griffin 2013). 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.
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:
Adults: Classified as a short-to-intermediate-acting benzodiazepine; classification based on benzodiazepines with half-life of <40 hours (Griffin 2013).
Indication specific duration:
Anesthesia premedication: Adults: IM, IV: ~6 to 8 hours.
Absorption: IM: Rapid and complete absorption; Oral: Readily absorbed.
Distribution:
Neonates (GA ≥37 weeks): 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%).
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