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LORazepam

Pronunciation

(lor A ze pam)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Concentrate, Oral:

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

Generic: 2 mg/mL (30 mL)

Solution, Injection:

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

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

Solution, Intravenous:

Generic: 100 mg/100 mL (100 mL); 100 mg/100 mL in NaCl 0.9% (100 mL); 60 mg/60 mL in NaCl 0.9% (60 mL [DSC])

Tablet, Oral:

Ativan: 0.5 mg, 1 mg [DSC]

Ativan: 1 mg [scored]

Ativan: 2 mg [DSC]

Ativan: 2 mg [scored]

Generic: 0.5 mg, 1 mg, 2 mg

Brand Names: U.S.

  • Ativan
  • LORazepam Intensol

Pharmacologic Category

  • Anticonvulsant, Benzodiazepine
  • Benzodiazepine

Pharmacology

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.

Absorption

IM: Rapid and complete absorption; Oral: Readily absorbed

Distribution

IV: Vd: Crosses the blood brain barrier

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

Pediatric patients (Chamberlain 2012):

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: 1.3 L/kg

Metabolism

Hepatic; rapidly conjugated to inactive compounds

Excretion

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

Onset of Action

Anticonvulsant: IV: Within 10 minutes

Hypnosis: IM: 20 to 30 minutes

Sedation: IV: Within 2 to 3 minutes (Greenblatt 1983)

Time to Peak

IM: ≤3 hours; Oral: ~2 hours; Sublingual tablet [Canadian product]: 1 hour

Duration of Action

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

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: ~12 hours; IV: ~14 hours; IM: ~13 to 18 hours (Greenblatt 1983); End-stage renal disease (ESRD): ~18 hours

Protein Binding

~91

Use: Labeled Indications

Anxiety (oral): Management of anxiety disorders, short-term (≤4 months) relief of anxiety symptoms, or anxiety associated with depressive symptoms, or anxiety/stress-associated insomnia.

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

Anesthesia premedication (sublingual) [Canadian product]: Anesthesia premedication to relieve anxiety prior to surgical procedures.

Status epilepticus (parenteral): Treatment of status epilepticus.

Off Label Uses

Agitation in the ICU patient

Based on the American Society of Critical Care Medicine guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit (ICU), intravenous lorazepam may be given for the management of agitation in these patients; however, in mechanically-ventilated patients, nonbenzodiazepine sedation may be preferred due to suggested increases in duration of mechanical ventilation, ICU length of stay, and incidence of delirium with benzodiazepines.

Alcohol withdrawal delirium

Based on the American Society of Addiction Medicine guidelines for the management of alcohol withdrawal delirium, lorazepam has been recommended for the management of this condition [Mayo-Smith 2004].

Alcohol withdrawal syndrome

Based on the American Society of Addiction Medicine guidelines for the treatment of alcohol withdrawal syndrome, lorazepam given for alcohol withdrawal is effective and recommended in the management of this condition [Mayo-Smith 1997].

Chemotherapy-associated nausea and vomiting (adjunct or breakthrough) (adults)

Based on the American Society of Clinical Oncology antiemetic guidelines for chemotherapy associated nausea and vomiting, lorazepam may be given as an adjunct for the management of chemotherapy-associated nausea and vomiting and for breakthrough episodes in adults [Basch 2011].

Chemotherapy-associated nausea and vomiting (adjunct or breakthrough) (children/adolescents)

For pediatrics, clinical experience suggests the utility of lorazepam in managing breakthrough nausea and vomiting [Dupuis 2003]; however, additional data may be necessary to further define the role of lorazepam in children for chemotherapy-associated nausea and vomiting.

Chemotherapy-associated nausea and vomiting (anticipatory) (children/adolescents)

Based on the Pediatric Oncology Group of Ontario (POGO) Guidelines for Prevention and Treatment of Anticipatory Nausea and Vomiting Due to Chemotherapy in Pediatric Cancer Patients, lorazepam may be given to prevent or treat anticipatory nausea and vomiting in children [Dupuis 2014].

Partial complex seizures (refractory)

Data from a limited number of patients studied suggests that adjunctive use of lorazepam may be beneficial for the treatment of partial complex seizures [Walker 1984]; additional data may be necessary to further define the role of lorazepam in this condition.

Psychogenic catatonia

Data from a limited number of patients in a small number of studies suggest that lorazepam may be beneficial for the treatment of psychogenic catatonia [Bush 1996], [Rosebush 1990]; clinical experience also suggests the utility of lorazepam in managing psychogenic catatonia [England 2011], [Rosebush 2010]. Additional data may be necessary to further define the role of lorazepam in this condition.

Rapid tranquilization of the agitated patient

Based on the Expert Consensus Guidelines on the Treatment of Behavioral Emergencies, lorazepam may be given to rapidly tranquilize the agitated patient [Allen 2005]. Based on the American Association for Emergency Psychiatry Project BETA Psychopharmacology Workgroup, benzodiazepines are recommended as first-line for agitation due to alcohol or benzodiazepine withdrawal or intoxication due to a CNS stimulant (eg, amphetamines) and second-line for agitation associated with psychosis in patients with known psychiatric disorders [Wilson 2012].

Clinical experience also suggests the utility of lorazepam in managing the agitated patient [Battaglia 2005], [ De Fruyt 2004], [Zeller 2010].

Status epilepticus (infants, children, and adolescents)

Based on the American Society of Pediatrics Statement on Drugs for Pediatric Emergencies, Neurocritical Care Society Guidelines for the Evaluation and Management of Status Epilepticus, and American Epilepsy Society Guidelines for the Treatment of Convulsive Status Epilepticus in Children and Adults, lorazepam is effective and recommended in the management of status epilepticus in infants, children, and adolescents.

Contraindications

Hypersensitivity to lorazepam, any component of the formulation, or other benzodiazepines (cross-sensitivity with other benzodiazepines may exist); acute narrow-angle glaucoma; severe respiratory insufficiency (except during mechanical ventilation)

Parenteral: Additional contraindications: Hypersensitivity to polyethylene glycol, propylene glycol, or benzyl alcohol; sleep apnea; intra-arterial injection; use in premature infants

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

Dosing: Adult

Anxiety disorder: Oral: Initial: 2 to 3 mg daily in 2 to 3 divided doses; usual dose: 2 to 6 mg daily in divided doses; however, daily dose may vary from 1 to 10 mg/day

Insomnia due to anxiety or stress: Oral:

<65 years: 0.5 to 2 mg at bedtime (Winkelman 2015)

≥65 years: 0.5 to 1 mg at bedtime (Winkelman 2015)

Note: The manufacturer recommends higher dosing (ie, 2 to 4 mg at bedtime); however, generally, it is a safer approach to employ the above recommended doses.

Premedication for anesthesia:

IM: 0.05 mg/kg administered 2 hours before surgery (maximum dose: 4 mg)

IV: 0.044 mg/kg administered 15 to 20 minutes before surgery (usual dose: 2 mg; maximum dose: 4 mg). Note: Doses >2 mg should generally not be exceeded in patients >50 years.

Sublingual tablet [Canadian product]: 0.05 mg/kg 1 to 2 hours before surgery (maximum dose: 4 mg)

Status epilepticus: IV:

American Epilepsy Society and Neurocritical Care Society recommendations: 0.1 mg/kg (maximum dose: 4 mg) given at a maximum rate of 2 mg/minute; may repeat in 5 to 10 minutes (AES [Glauser 2016]; NCS [Brophy 2012]). Note: Dilute dose 1:1 with saline.

Manufacturer's labeling: 4 mg given slowly (2 mg/minute); may repeat in 10 to 15 minutes. May be given IM, but IV preferred.

Agitation in the ICU patient (off-label use): IV: Loading dose: 0.02 to 0.04 mg/kg (maximum single dose: 2 mg); Maintenance: 0.02 to 0.06 mg/kg every 2 to 6 hours as needed or 0.01 to 0.1 mg/kg/hour; maximum dose: ≤10 mg/hour (Barr 2013)

Alcohol withdrawal delirium (off-label use) (Mayo-Smith 2004):

IV: 1 to 4 mg every 5 to 15 minutes until calm, then every hour as needed to maintain light somnolence

IM: 1 to 4 mg every 30 to 60 minutes until calm, then every hour as needed to maintain light somnolence

Alcohol withdrawal syndrome (off-label use) (Mayo-Smith, 1997):

Oral, IM, IV (fixed-dose regimen): 2 mg every 6 hours for 4 doses, then 1 mg every 6 hours for 8 additional doses

Oral, IM, IV (symptom-triggered regimen): 2 to 4 mg every 1 hour as needed; dose determined by a validated severity assessment scale

Chemotherapy-associated nausea and vomiting (off-label use): Breakthrough nausea/vomiting or as adjunct to standard antiemetics: Oral, IV, Sublingual (off-label route): 0.5 to 2 mg every 6 hours as needed (Lohr 2008)

Partial complex seizures, refractory (off-label use): Oral: 1 mg twice daily; increase biweekly in increments of 1 mg twice daily until seizures stop or side effects occur (Walker, 1984); however, additional data may be necessary to further define the role of lorazepam in this condition

Psychogenic catatonia (off-label use):

IM, Sublingual (off-label route): 1 to 2 mg; repeat dose in 3 hours then again in another 3 hours if initial and subsequent doses, respectively, are ineffective (Rosebush, 1990; Rosebush 2010); however, additional data may be necessary to further define the role of lorazepam in this condition

or

Oral, IM, IV: Initial: 1 mg; may repeat in 5 minutes if necessary. If initial challenge is unsuccessful, may increase dose up to 4 to 8 mg per day; may continue treatment for up to 5 days (Bush, 1996); however, additional data may be necessary to further define the role of lorazepam in this condition

Rapid tranquilization of the agitated patient (off-label use): Oral, IM, IV: 1 to 3 mg administered every 30 to 60 minutes; may be administered with an antipsychotic (eg, haloperidol) (Allen 2005; Battaglia 2005; De Fruyt 2004; Wilson 2012). Note: When administering IM, may consider a lower initial dose (eg, 0.5 mg) (Allen 2005).

Dosage adjustment for lorazepam with concomitant medications: Probenecid or valproic acid: Reduce lorazepam dose by 50%

Dosing: Geriatric

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

Anxiety disorder: Oral: Initial: 1 to 2 mg daily in divided doses

Dosing: Pediatric

Chemotherapy-associated nausea and vomiting (off-label use):

Anticipatory nausea/vomiting (prevention and treatment): Infants ≥1 month, Children, and Adolescents: Oral: 0.04 to 0.08 mg/kg/dose (maximum dose: 2 mg) once at bedtime the evening prior to chemotherapy and once the next day before chemotherapy (Dupuis 2014)

Breakthrough nausea/vomiting: Children ≥2 years and Adolescents: IV: 0.025 to 0.05 mg/kg/dose (maximum dose: 2 mg) every 6 hours as needed (Dupuis 2003); however, additional data may be necessary to further define the role of lorazepam in children for chemotherapy-associated nausea and vomiting

Status epilepticus: Infants, Children, and Adolescents (off-label use):

American Epilepsy Society and Neurocritical Care Society recommendations: IV: 0.1 mg/kg (maximum dose: 4 mg) given at a maximum rate of 2 mg/minute; may repeat in 5 to 10 minutes (AES [Glauser 2016]; NCS [Brophy 2012]). Note: Dilute dose 1:1 with saline.

American Academy of Pediatrics recommendation: IV, IM: 0.05 to 0.1 mg/kg (maximum dose: 4 mg); may repeat dose every 10 to 15 minutes if seizure continues (AAP [Hegenbarth 2008])

Dosage adjustment for lorazepam with concomitant medications: Probenecid or valproic acid: Reduce lorazepam dose by 50%

Dosing: Renal Impairment

Oral: No dosage adjustment necessary (Aronoff 2007).

Parenteral:

Mild-to-moderate impairment: 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.

Severe impairment or failure: Use is not recommended.

Dosing: Hepatic Impairment

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: Use is not recommended.

Reconstitution

IV injection: According to the manufacturer, dilute IV dose prior to use with an equal volume of compatible diluent (D5W, NS, SWFI).

Infusion: Precipitation may occur upon dilution when preparing an infusion. Use 2 mg/mL injectable vial to prepare; there may be decreased stability when using 4 mg/mL vial. Dilute to ≤1 mg/mL with a compatible diluent in a non-PVC (eg, polyolefin, glass) container (consult parenteral admixture resource for additional detailed recommendations). Can also be administered undiluted (up to 4 mg/mL) via infusion into a central vein or into a peripheral vein with a running compatible maintenance IV solution (Johnson 2002).

IM: Administer undiluted.

Extemporaneously Prepared

Note: Commercial oral solution is available (2 mg/mL)

Two different 1 mg/mL oral suspensions may be made from different generic lorazepam tablets (Mylan Pharmaceuticals or Watson Laboratories), sterile water, Ora-Sweet, and Ora-Plus.

Mylan tablets: Place one-hundred-eighty 2 mg tablets in a 12-ounce amber glass bottle; add 144 mL of sterile water to disperse the tablets; shake until slurry is formed. Add 108 mL Ora-Plus in incremental proportions; then add a quantity of Ora-Sweet sufficient to make 360 mL. Label "shake well" and "refrigerate". Stable for 91 days when stored in amber glass prescription bottles at room temperature or refrigerated (preferred).

Watson tablets: Place one-hundred-eighty 2 mg tablets in a 12-ounce amber glass bottle; add 48 mL sterile water to disperse the tablets; shake until slurry is formed. Add 156 mL of Ora-Plus in incremental proportions; then add a quantity of Ora-Sweet sufficient to make 360 mL. Label "shake well" and "refrigerate". Store in amber glass prescription bottles. Stable for 63 days at room temperature or 91 days refrigerated.

Lee ME, Lugo RA, Rusho WJ, et al, "Chemical Stability of Extemporaneously Prepared Lorazepam Suspension at Two Temperatures," J Pediatr Pharmacol Ther, 2004, 9(4):254-58.

Administration

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.

Continuous IV infusion (off-label administration mode; Barr 2013) solutions should have an in-line filter and the solution should be checked frequently for possible precipitation (Grillo 1996).

Oral: Lorazepam 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.

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

Storage

Parenteral: Intact vials should be refrigerated (room temperature storage information may be available; contact product manufacturer to obtain current recommendations). Protect from light. Parenteral admixture in D5W, LR, or NS is stable at room temperature (25°C) for 24 hours (consult parenteral admixture resource for additional detail).

Oral concentrate: Store at colder room temperature or refrigerate at 2°C to 8°C (36°F to 46°F). Discard open bottle after 90 days.

Oral tablet: Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Sublingual tablet [Canadian product]: Store at 15°C to 25°C (59°F to 77°F). Protect from light.

Drug Interactions

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

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Benznidazole: May enhance the adverse/toxic effect of Products Containing Propylene Glycol. Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

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

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 patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. 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. Consider therapy modification

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

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

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Fosphenytoin: Benzodiazepines may increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Monitor therapy

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone 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. Consider therapy modification

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

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

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

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

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

Melatonin: May enhance the sedative effect of Benzodiazepines. 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. 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 adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

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

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

OLANZapine: May enhance the adverse/toxic effect of Benzodiazepines. Management: Avoid concomitant use of parenteral benzodiazepines and IM olanzapine due to risks of additive adverse events (e.g., cardiorespiratory depression). Olanzapine prescribing information provides no specific recommendations regarding oral administration. Avoid combination

Opioid Analgesics: CNS Depressants may enhance the CNS depressant effect of Opioid Analgesics. Management: Avoid concomitant use of opioid analgesics 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. Consider therapy modification

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

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

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

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Phenytoin: Benzodiazepines may increase the serum concentration of Phenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Monitor therapy

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

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

Probenecid: May increase the serum concentration of LORazepam. Consider therapy modification

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

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

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

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sodium Oxybate: Benzodiazepines may enhance the CNS depressant effect of Sodium Oxybate. 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. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol 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. Consider therapy modification

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

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Consider therapy modification

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

Valproate Products: May increase the serum concentration of LORazepam. Consider therapy modification

Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. 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. Consider therapy modification

Adverse Reactions

Frequency not always defined.

Cardiovascular: Hypotension (≤2%)

Central nervous system: Sedation (≤16%), dizziness (≤7%), drowsiness (2% to 4%), unsteadiness (3%), headache (1%), coma (≤1%), stupor (≤1%), aggressive behavior, agitation, akathisia, amnesia, anxiety, central nervous system stimulation, disinhibition, disorientation, dysarthria, euphoria, excitement, extrapyramidal reaction, fatigue, hostility, hypothermia, irritability, mania, memory impairment, outbursts of anger, psychosis, seizures, sleep apnea (exacerbation), sleep disturbances, slurred speech, suicidal behavior, suicidal ideation, vertigo

Dermatologic: Alopecia, skin rash

Gastrointestinal: Changes in appetite, constipation

Endocrine & metabolic: Change in libido, hyponatremia, SIADH

Genitourinary: Impotence, orgasm disturbance

Hematologic & oncologic: Agranulocytosis, pancytopenia, thrombocytopenia

Hepatic: Increased serum alkaline phosphatase, increased serum bilirubin, increased serum transaminases, jaundice

Hypersensitivity: Anaphylaxis, anaphylactoid reaction, hypersensitivity reaction

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

Neuromuscular & skeletal: Weakness (≤4%)

Ophthalmic: Visual disturbances (including diplopia and blurred vision)

Respiratory: Respiratory failure (1% to 2%), apnea (1%), hypoventilation (≤1%), exacerbation of obstructive pulmonary disease, nasal congestion, respiratory depression, worsening of sleep apnea

<1% (Limited to important or life-threatening): Abnormal gait, abnormal hepatic function tests, abnormality in thinking, acidosis, cardiac arrhythmia, ataxia, blood coagulation disorder, bradycardia, cardiac arrest, cardiac failure, cerebral edema, confusion, convulsions, cystitis, decreased mental acuity, delirium, depression, drug dependence (with prolonged use), drug toxicity (polyethylene glycol or propylene glycol poisoning [prolonged IV infusion]), excessive crying, gastrointestinal hemorrhage, hallucinations, hearing loss, heart block, hematologic abnormality, hepatotoxicity, hypertension, hyperventilation, hyporeflexia, infection, injection site reaction, myoclonus, neuroleptic malignant syndrome, paralysis, pericardial effusion, pheochromocytoma (aggravation), pneumothorax, pulmonary edema, pulmonary hemorrhage, pulmonary hypertension, seizure, tachycardia, urinary incontinence, ventricular arrhythmia, withdrawal syndrome

ALERT: U.S. Boxed Warning

Risks from concomitant use with opioids:

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

Warnings/Precautions

Concerns related to adverse effects:

• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients.

Disease-related concerns:

• Drug abuse: Risk of dependence increases in patients with a history of alcohol or drug abuse and those with significant personality disorders; use with caution in these patients. Tolerance, psychological and physical dependence may also occur with higher dosages and prolonged use. The risk of dependence is decreased with short-term treatment (2 to 4 weeks); evaluate the need for continued treatment prior to extending therapy duration.

• 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. Parenteral use is not recommended in patients with hepatic failure.

• Impaired gag reflex: Use with caution in patients with an impaired gag reflex.

• Psychiatric disorders: Preexisting depression may emerge or worsen during therapy. Not recommended for use in primary depressive or psychotic disorders. Should not be used in patients at risk for suicide without adequate antidepressant treatment.

• Renal impairment: Use with caution in patients with renal impairment. Parenteral use is not recommended in patients with renal failure.

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

Concurrent drug therapy issues:

• Concomitant use with opioids: [US Boxed Warning]: Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in 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. 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.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

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

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

• Pediatrics: In pediatric and neonatal patients <3 years, the repeated or lengthy exposure to sedatives or anesthetics during surgery/procedures may have detrimental effects on the child's brain development and may contribute to various cognitive and behavioral problems. Epidemiological studies have reported various cognitive and behavioral problems including neurodevelopmental delay (and related diagnoses), learning disabilities, and ADHD. Clinical data suggest that single, relatively short exposures are not likely to have similar negative effects. Further studies are needed to fully characterize findings and ensure that these findings are not related to underlying conditions or the procedure itself. No specific anesthetic/sedative has been found to be safer. For elective procedures, risk vs benefits should be evaluated and discussed with parents/caregivers/patients; critical surgeries should not be delayed (FDA 2016).

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.

• Propylene glycol: Parenteral formulation may contain propylene glycol; large amounts are potentially toxic and have been associated with hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer's labeling. May consider using enteral delivery of lorazepam tablets to decrease the risk of propylene glycol toxicity (Lugo 1999).

Other warnings/precautions:

• 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.

• Hypnotic: Appropriate use: As a hypnotic, should be used only after evaluation of potential causes of sleep disturbance. Failure of sleep disturbance to resolve after 7 to 10 days may indicate psychiatric or medical illness. A worsening of insomnia or the emergence of new abnormalities of thought or behavior may represent unrecognized psychiatric or medical illness and requires immediate and careful evaluation.

• 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 anticonvulsant 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.

• Withdrawal: Rebound or withdrawal symptoms may occur following abrupt discontinuation or large decreases in dose. Use caution when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms. Flumazenil may cause acute withdrawal in patients receiving long-term benzodiazepine therapy.

Monitoring Parameters

Respiratory and cardiovascular status, blood pressure, heart rate, symptoms of anxiety

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, osmolal gap; Note: An osmolal gap of ≥10 was predictive of elevated propylene glycol concentrations; values of ≥12 suggest propylene glycol toxicity (Barnes 2006; Yahwak 2008)

Critically-ill patients: Monitor depth of sedation with either the Richmond Agitation-Sedation Scale (RASS) or Sedation-Agitation Scale (SAS) (Barr 2013)

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).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, headache, or injection site irritation. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), hallucinations, behavioral changes, change in balance, confusion, memory impairment, severe loss of strength and energy, severe dizziness, passing out, vision changes, muscle weakness, dark urine, jaundice, difficulty breathing, slow breathing, or shallow breathing (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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