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Medication Safety Issues
Sound-alike/look-alike issues:
LORazepam may be confused with ALPRAZolam, clonazePAM, diazepam, Lovaza®, temazepam, zolpidem
Ativan® may be confused with Ambien®, Atarax®, Atgam®, Avitene®
Injection dosage form contains propylene glycol. Monitor for toxicity when administering continuous lorazepam infusions.
Pronunciation
(lor A ze pam)
U.S. Brand Names
Generic Available
Yes: Injection, tablet
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Oral: Management of anxiety disorders or short-term (?4 months) relief of the symptoms of anxiety or anxiety associated with depressive symptoms
I.V.: Status epilepticus, amnesia, sedation
Use: Dental
Short-term relief of anxiety prior to dental appointment
Use: Unlabeled/Investigational
Ethanol detoxification; insomnia; psychogenic catatonia; partial complex seizures; agitation (I.V.); antiemetic adjunct
Restrictions
C-IV
Pregnancy Risk Factor
D
Pregnancy Considerations
Teratogenic effects have been observed in some animal studies. Lorazepam crosses the human placenta. Respiratory depression, withdrawal symptoms, or hypotonia may occur if administered late in pregnancy or near the time of delivery.
Lactation
Enters breast milk/not recommended (AAP rates “of concern”)
Breast-Feeding Considerations
Sedation and impaired nursing may occur in infants exposed to lorazepam from breast milk.
Contraindications
Hypersensitivity to lorazepam or any component of the formulation (cross-sensitivity with other benzodiazepines may exist); acute narrow-angle glaucoma; sleep apnea (parenteral); intra-arterial injection of parenteral formulation; severe respiratory insufficiency (except during mechanical ventilation)
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: Use with caution in patients with a history of drug abuse, alcoholism, or significant personality disorders; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use. Risk of dependence increases with higher dosage and longer duration of therapy.
• Hepatic impairment: Use with caution in patients with hepatic impairment. Dose adjustment may be needed. May worsen hepatic encephalopathy.
• Impaired gag reflux: Use with caution in patients with an impaired gag reflux.
• Psychiatric disorders: Use caution in patients with depression, particularly if suicidal risk may be present. Pre-existing depression may emerge or worsen during therapy. Not recommended for use in primary depressive or psychotic disorders.
• Renal impairment: Use with caution in patients with renal impairment.
• 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:
• CNS depressants/psychoactive medications: Use with caution in patients receiving other CNS depressants or psychoactive medication; effects with other sedative drugs or ethanol may be potentiated.
Special populations:
• Debilitated patients: Use with caution in debilitated patients; initial doses should be at the lower end of dosing range.
• Elderly: Use with caution in the elderly; benzodiazepines have been associated with falls and traumatic injury. Initial doses should 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: Safety and efficacy have not been established in children <12 years of age.
Dosage form specific issues:
• Benzyl alcohol: Some products may contain benzyl alcohol which has been associated with "gasping syndrome" in neonates.
• Polyethylene glycol: Parenteral formulation contains polyethylene glycol. May be associated with toxicity in high-dose and/or longer-term therapy.
• Propylene glycol: Parenteral formulation contains propylene glycol (PG). May be associated with dose-related toxicity and can occur ?48 hours after initiation of lorazepam. Limited data suggest increased risk of PG accumulation at doses of ?6 mg/hour for 48 hours or more (Nelson, 2008). Consider monitoring for signs of toxicity which may include acute renal failure, lactic acidosis, and/or osmol gap. In high-risk patients requiring higher doses/extended treatment durations, use of enteral delivery of lorazepam tablets may be beneficial (Jacobi, 2002).
Other warnings/precautions:
• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties.
• 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 7-10 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.
• 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.
Adverse Reactions
>10%:
Central nervous system: Sedation
Respiratory: Respiratory depression
1% to 10%:
Cardiovascular: Hypotension
Central nervous system: Akathisia, amnesia, ataxia, confusion, depression, disorientation, dizziness, headache
Dermatologic: Dermatitis, rash
Gastrointestinal: Changes in appetite, nausea, weight gain/loss
Neuromuscular & skeletal: Weakness
Ocular: Visual disturbances
Respiratory: Apnea, hyperventilation, nasal congestion
<1% or frequency not defined: Asthenia, blood dyscrasias, disinhibition, euphoria, fatigue, increased salivation, menstrual irregularities, physical and psychological dependence (with prolonged use), reflex slowing, polyethylene glycol or propylene glycol poisoning (prolonged I.V. infusion), suicidal ideation, seizure, vertigo
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Clozapine: Benzodiazepines may enhance the adverse/toxic effect of Clozapine. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other 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
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce dosage 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. Risk D: 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. Risk C: Monitor therapy
Probenecid: May decrease the metabolism of LORazepam. Risk D: Consider therapy modification
Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk D: Consider therapy modification
Valproic Acid: May decrease the metabolism of LORazepam. Risk D: Consider therapy modification
Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid or limit ethanol (may increase CNS depression).
Herb/Nutraceutical: Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).
Storage
I.V.: Intact vials should be refrigerated. Protect from light. Do not use discolored or precipitate-containing solutions. May be stored at room temperature for up to 60 days. Parenteral admixture is stable at room temperature (25°C) for 24 hours.
Tablet: Store at room temperature.
Reconstitution
Injection: Dilute with equal volume of compatible diluent (D5W, NS, SWI).
Infusion: Use 2 mg/mL injectable vial to prepare; there may be deceased stability when using 4 mg/mL vial. Dilute ?1 mg/mL and mix in glass bottle. Precipitation may develop. Can also be administered undiluted via infusion.
Compatibility
Variable stability (consult detailed reference) in D5W, LR, NS.
Y-site administration: Compatible: Acyclovir, alatrofloxacin, albumin, allopurinol, amifostine, amikacin, amphotericin B cholesteryl sulfate complex, amsacrine, atracurium, bumetanide, cefepime, cefotaxime, ciprofloxacin, cisatracurium, cisplatin, cladribine, clonidine, co-trimoxazole, cyclophosphamide, cytarabine, dexamethasone sodium phosphate, diltiazem, dobutamine, docetaxel, dopamine, doxorubicin, doxorubicin liposome, epinephrine, erythromycin lactobionate, etomidate, etoposide phosphate, famotidine, fentanyl, filgrastim, fluconazole, fludarabine, fosphenytoin, furosemide, gatifloxacin, gemcitabine, gentamicin, granisetron, haloperidol, heparin, hydrocortisone sodium succinate, hydromorphone, ketanserin, labetalol, levofloxacin, linezolid, melphalan, methotrexate, metronidazole, midazolam, milrinone, morphine, nicardipine, nitroglycerin, norepinephrine, paclitaxel, pancuronium, piperacillin, piperacillin/tazobactam, potassium chloride, propofol, ranitidine, remifentanil, tacrolimus, teniposide, thiotepa, vancomycin, vecuronium, vinorelbine, zidovudine. Incompatible: Aldesleukin, aztreonam, floxacillin, idarubicin, imipenem/cilastatin, omeprazole, ondansetron, sargramostim, sufentanil. Variable (consult detailed reference): Foscarnet, thiopental, TPN.
Compatibility in syringe: Compatible: Cimetidine, hydromorphone. Incompatible: Sufentanil. Variable (consult detailed reference): Ranitidine.
Compatibility when admixed: Incompatible: Buprenorphine, dexamethasone sodium phosphate with diphenhydramine and metoclopramide.
Mechanism of Action
Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization.
Pharmacodynamics/Kinetics
Onset of action:
Hypnosis: I.M.: 20-30 minutes
Sedation: I.V.: 5-20 minutes
Anticonvulsant: I.V.: 5 minutes, oral: 30-60 minutes
Duration: 6-8 hours
Absorption: Oral, I.M.: Prompt
Distribution:
Vd: Neonates: 0.76 L/kg, Adults: 1.3 L/kg; crosses placenta; enters breast milk
Protein binding: 85%; free fraction may be significantly higher in elderly
Metabolism: Hepatic to inactive compounds
Bioavailability: Oral: 90%
Half-life elimination: Neonates: 40.2 hours; Older children: 10.5 hours; Adults: 12.9 hours; Elderly: 15.9 hours; End-stage renal disease: 32-70 hours
Time to peak: Oral: 2 hours
Excretion: Urine; feces (minimal)
Dosage
Antiemetic (unlabeled use):
Children 2-15 years: I.V.: 0.05 mg/kg (up to 2 mg/dose) prior to chemotherapy
Adults: Oral, I.V. (Note: May be administered sublingually; not a labeled route): 0.5-2 mg every 4-6 hours as needed
Anxiety and sedation (unlabeled in children except for oral use in children >12 years):
Infants and Children: Oral, I.M., I.V.: Usual: 0.05 mg/kg/dose (range: 0.02-0.09 mg/kg) every 4-8 hours
I.V.: May use smaller doses (eg, 0.01-0.03 mg/kg) and repeat every 20 minutes, as needed to titrate to effect
Adults: Oral: 1-10 mg/day in 2-3 divided doses; usual dose: 2-6 mg/day in divided doses
Elderly: 0.5-4 mg/day; initial dose not to exceed 2 mg
Insomnia: Adults: Oral: 2-4 mg at bedtime
Preoperative: Adults:
I.M.: 0.05 mg/kg administered 2 hours before surgery (maximum: 4 mg/dose)
I.V.: 0.044 mg/kg 15-20 minutes before surgery (usual maximum: 2 mg/dose)
Preprocedural anxiety (dental use): Adults: Oral: 1-2 mg 1 hour before procedure
Operative amnesia: Adults: I.V.: Up to 0.05 mg/kg (maximum: 4 mg/dose)
Sedation (preprocedure): Infants and Children (unlabeled):
Oral, I.M., I.V.: Usual: 0.05 mg/kg (range: 0.02-0.09 mg/kg)
I.V.: May use smaller doses (eg, 0.01-0.03 mg/kg) and repeat every 20 minutes, as needed to titrate to effect
Status epilepticus: I.V.:
Infants and Children (unlabeled): 0.05-0.1 mg/kg (maximum: 4 mg/dose) slow I.V. (maximum rate: 2 mg/minute); may repeat every 10-15 minutes as needed (Hegenbarth, 2008; Sabo-Graham, 1998)
Adults: 4 mg/dose slow I.V. (maximum rate: 2 mg/minute); may repeat in 10-15 minutes; usual maximum dose: 8 mg
Rapid tranquilization of agitated patient (administer every 30-60 minutes): Adults:
Oral: 1-2 mg
I.M.: 0.5-1 mg
Average total dose for tranquilization: Oral, I.M.: 4-8 mg
Agitation in the ICU patient (unlabeled): Adults:
I.V.: 0.02-0.06 mg/kg every 2-6 hours
I.V. infusion: 0.01-0.1 mg/kg/hour
Concurrent use of probenecid or valproic acid: Reduce lorazepam dose by 50%
Dosage adjustment in renal impairment: I.V.: Risk of propylene glycol toxicity. Monitor closely if using for prolonged periods of time or at high doses.
Dosage adjustment in hepatic impairment: Use cautiously.
Dental Usual Dosing
Anxiety and sedation: Adults: Oral: 1-10 mg/day in 2-3 divided doses; usual dose: 2-6 mg/day in divided doses
Preoperative: Adults:
I.M.: 0.05 mg/kg administered 2 hours before surgery (maximum: 4 mg/dose)
I.V.: 0.044 mg/kg 15-20 minutes before surgery (usual maximum: 2 mg/dose)
Preprocedural anxiety: Adults: Oral: 1-2 mg 1 hour before procedure
Administration: I.M.
Should be administered deep into the muscle mass.
Administration: I.V.
Continuous infusion solutions should have an in-line filter and the solution should be checked frequently for possible precipitation. Avoid intra-arterial administration. Monitor I.V. site for extravasation.
Administration: I.V. Detail
Dilute I.V. dose with equal volume of compatible diluent (D5W, NS, SWI).
Monitoring Parameters
Respiratory and cardiovascular status, blood pressure, heart rate, symptoms of anxiety
Clinical signs of propylene glycol toxicity (for continuous high-dose and/or long duration intravenous use): Serum creatinine, BUN, serum lactate, osmol gap
Reference Range
Therapeutic: 50-240 ng/mL (SI: 156-746 nmol/L)
Patient Education
Oral: Take exactly as directed; do not increase dose or frequency. Drug may cause physical and/or psychological dependence. Do not use alcohol or other prescription or OTC medications (especially pain medications, sedatives, antihistamines, or hypnotics) without consulting prescriber. Maintain adequate hydration unless instructed to restrict fluid intake. You may experience drowsiness, lightheadedness, impaired coordination, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, or dry mouth (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruit, or fiber may help); altered sexual drive or ability (reversible); or photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight). Report persistent CNS effects (eg, confusion, depression, increased sedation, excitation, headache, agitation, insomnia or nightmares, dizziness, fatigue, impaired coordination, changes in personality, or changes in cognition); changes in urinary pattern; chest pain, palpitations, or rapid heartbeat; muscle cramping, weakness, tremors, or rigidity; ringing in ears or visual disturbances; excessive perspiration; excessive GI symptoms (cramping, constipation, vomiting, anorexia); or worsening of condition. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication; use appropriate contraceptive measures. Do not breast-feed.
Geriatric Considerations
Because lorazepam is relatively short-acting with an inactive metabolite, it is a preferred agent to use in elderly patients when a benzodiazepine is indicated.
Additional Information
Oral doses >0.09 mg/kg produced increased ataxia without increased sedative benefit vs lower doses; preferred anxiolytic when I.M. route needed. Abrupt discontinuation after sustained use (generally >10 days) may cause withdrawal symptoms.
Anesthesia and Critical Care Concerns/Other Considerations
Lorazepam 2 mg/mL and 4 mg/mL each contain propylene glycol 830 mg/mL (80% v/v). In addition, lorazepam 2 mg/mL oral solution (Intensol™) contains propylene glycol.
Agitation in the ICU Patient: Lorazepam has a slower onset of action than midazolam or diazepam, making it less useful for treatment of acute agitation. The polyethylene glycol and propylene glycol solvents in lorazepam injection can accumulate and lead to reversible acute tubular necrosis, lactic acidosis, and hyperosmolar states with prolonged, high-dose infusions.
A prospective, observational study was performed in a medical intensive care unit evaluating patients receiving high-dose lorazepam (?10 mg/hour) infusions (Arroliga, 2004). The primary objective was to evaluate the relationship between high-dose lorazepam and serum propylene glycol concentrations. Nine patients met the criteria for entry. Baseline creatinine clearances were 50-100 mL/minute. Propylene glycol accumulation was observed in these patients receiving high-dose lorazepam infusions for ?48 hours. A significant correlation between high-dose lorazepam infusion rate and serum propylene glycol concentrations was observed. However, osmol gap was the strongest predictor (R2 = 0.80) of serum propylene glycol concentrations. Study findings suggest that in critically ill adults with normal renal function, serum propylene glycol concentrations may be predicted by the osmol gap. Based on these findings, propylene glycol accumulation may occur as early as 48 hours when using high-dose lorazepam infusions.
To calculate osmolarity: [2 x sodium (mEq/L)] + [glucose (mg/dL)/18] + [BUN (mg/dL)/2.8]
To calculate osmol gap (normal range: 0-5): (measured osmolality minus calculated osmolarity)
However, Nelsen et al (2008) conducted a prospective evaluation of 50 adult critically-ill patients (median APACHE II = 20) receiving lorazepam continuous infusion for ?48 hours in the surgical, medical or burn/trauma ICU. Eight patients exhibited PG accumulation (>25 mg/dL) associated with a median lorazepam infusion rate of 6.4 mg/hour, despite lack of correlation with osmolal gap or serum lactate levels. Of note, reduced clearance of PG correlated with increasing APACHE II scores.
Lorazepam is recommended for the sedation of most patients. Use a defined endpoint in titration of the dose. Use a system to minimize prolonged sedative effects. If patient has received high-dose or >7 days of continuous therapy, consider tapering infusion to prevent withdrawal symptoms.
In the MENDS trial, compared to dexmedetomidine the use of lorazepam for ICU sedation of mechanically-ventilated patients increased the number of days alive with delirium or coma. A nonsignificant increase in 28-day mortality was noted in the lorazepam group when compared to dexmedetomidine (27% vs 17%, respectively; p=0.18) (Pandharipande, 2007).
Cardiovascular Considerations
Hypotension may result in orthostatic lightheadedness or syncope. Benzodiazepines, as a class, may depress respiration. These medications may often be prescribed for difficulty in sleeping but may exacerbate sleep-disordered breathing.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Comment
In 2007, the FDA requested that all manufacturers of sedative-hypnotic drug products revise labeling to include a greater emphasis on the risks of adverse effects. These risks include severe allergic reactions (anaphylaxis, angioedema) and complex sleep-related behaviors, which may include sleep-driving (driving while not fully awake and with no memory of the event), making phone calls, and preparing and eating food while asleep.
There are two subtypes of GABA receptors (GABA-A and GABA-B) and three different benzodiazepine receptors (Bz1, Bz2, and Bz3). Benzodiazepine receptors and effects appear to be linked to the GABA-A receptors. Benzodiazepines do not bind to GABA-B receptors. The role of GABA-B receptors is unclear. Benzodiazepines have no specificity for benzodiazepine receptor subtypes.
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 or skeletal muscle relaxing effects. Psychological and physical dependence may occur with prolonged use of benzodiazepines. The onset of withdrawal symptoms is usually seen on the first day without drug and lasts 5-7 days in patients receiving short half-life benzodiazepines, whereas, the onset occurs after 5 days with a duration of 10-14 days after abrupt discontinuance of long half-life benzodiazepines. Risk factors for abuse include personal or family history of substance abuse and personality disorder.
Lorazepam is rapidly and completely absorbed after I.M. injection; undergoes phase II metabolism and, therefore, is less likely to be affected in patients with hepatic dysfunction.
Nursing: Physical Assessment/Monitoring
Assess other medications the patient may be taking for effectiveness and interactions. Oral: Assess for history of addiction; long-term use can result in dependence, abuse, or tolerance; periodically evaluate need for continued use. For inpatient use, institute safety measures and monitor effectiveness and adverse reactions. For outpatients, monitor therapeutic effectiveness and adverse reactions at beginning of therapy and periodically with long-term use. Taper dosage slowly when discontinuing. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse symptoms to report. I.V./I.M.: Monitor vital signs and CNS status (possible retrograde amnesia with I.V.), and ability to void. Maintain bedrest for 2-3 hours, and observe when up.
Oncology: Emetic Potential
Very low (<10%)
Oncology: Vesicant
No
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution: 2 mg/mL (1 mL, 10 mL); 4 mg/mL (1 mL, 10 mL)
Ativan®: 2 mg/mL (1 mL, 10 mL); 4 mg/mL (1 mL, 10 mL) [contains benzyl alcohol, polyethylene glycol 400, and propylene glycol]
Injection, solution [preservative free]: 2 mg/mL (1 mL); 4 mg/mL (1 mL)
Solution, oral [concentrate]:
Lorazepam Intensol™: 2 mg/mL (30 mL) [ethanol free, sugar free, dye free; contains propylene glycol]
Tablet: 0.5 mg, 1 mg, 2 mg
Ativan®: 0.5 mg
Ativan®: 1 mg, 2 mg [scored]
Pricing: U.S. (www.drugstore.com)
Concentrate (LORazepam Intensol)
2 mg/mL (30): $43.25
Tablets (Ativan)
0.5 mg (30): $77.34
1 mg (30): $90.08
2 mg (30): $139.33
Tablets (LORazepam)
1 mg (30): $14.99
2 mg (30): $21.99
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International Brand Names
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Last full review/revision September 2009
Content last modified September 2009
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