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Medication Safety Issues
Sound-alike/look-alike issues:
Lorazepam may be confused with alprazolam, clonazepam, diazepam, temazepam
Ativan® may be confused with 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
Canadian Brand Names
Pharmacologic Category
Use
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, preanesthesia for desired amnesia
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 Implications
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. May be associated with toxicity in high dose and/or longer term therapy.
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: Confusion, dizziness, akathisia, ataxia, headache, depression, disorientation, amnesia
Dermatologic: Dermatitis, rash
Gastrointestinal: Weight gain/loss, nausea, changes in appetite
Neuromuscular & skeletal: Weakness
Ocular: Visual disturbances
Respiratory: Nasal congestion, hyperventilation, apnea
<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
Clozapine: Benzodiazepines may enhance the adverse/toxic effect of clozapine (sedation, hypersalivation, hypotension, ataxia, delirium, and respiratory distress reported).
CNS depressants: Sedative effects and/or respiratory depression may be additive with CNS depressants; includes ethanol, barbiturates, opioid analgesics, and other sedative agents; monitor for increased effect
Loxapine: There are rare reports of significant respiratory depression, stupor, and/or hypotension with concomitant use of loxapine and lorazepam; use caution if concomitant administration of loxapine and CNS drugs is required
Probenecid: May increase the levels/effects of lorazepam; adjust lorazepam dose (decrease by 50%).
Theophylline: May partially antagonize some of the effects of benzodiazepines; monitor for decreased response; may require higher doses for sedation
Valproic acid derivatives: May increase the levels/effects of lorazepam; adjust lorazepam dose (decrease by 50%).
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): 0.1 mg/kg slow I.V. over 2-5 minutes; do not exceed 4 mg/single dose; may repeat second dose of 0.05 mg/kg slow I.V. in 5-10 minutes if needed
Adolescents: 0.07 mg/kg slow I.V. over 2-5 minutes; maximum: 4 mg/dose; may repeat in 5-10 minutes
Adults: 4 mg/dose slow I.V. over 2-5 minutes; may repeat in 5-10 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
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 (2-3 L/day of fluids) 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 contains propylene glycol 830 mg/mL (80% v/v).
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. Yaucher (2003) and colleagues recently performed a retrospective review of patients who received lorazepam infusions and developed increases in serum creatinine. Eight patients from the medical-surgical intensive care unit or burn unit were evaluated. Lorazepam infusions ranged from 2-28 mg/hour. The mean cumulative dose of lorazepam was 4305 mg and the mean propylene glycol level determined at the time of peak serum creatinine concentration was 1103 mcg/mL. The duration of lorazepam infusion and magnitude of serum creatinine concentration rise correlated (r: 0.60). Propylene glycol levels strongly correlated with both serum osmolality and osmol gap. These authors suggest that serum osmolality and osmol gap may be useful markers of propylene glycol toxicity. A recent case report described a critically-ill man who developed acute tubular necrosis while receiving a lorazepam infusion and sulfamethoxazole-trimethoprim (Hayman, 2003). The addition of sulfamethoxazole-trimethoprim contributed to the development of propylene glycol toxicity.
More recently, 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)
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.
Status Epilepticus: A randomized, double-blind trial (Treiman, 1998) evaluated the efficacy of four treatments in overt status epilepticus. Treatment arms were designed based upon accepted practices of North American neurologists. The treatments were: 1) lorazepam 0.1 mg/kg, 2) diazepam 0.15 mg/kg followed by phenytoin 18 mg/kg, 3) phenytoin 18 mg/kg alone, and 4) phenobarbital 15 mg/kg. Treatment was considered successful if the seizures were terminated (clinically and by EEG) within 20 minutes of start of therapy without seizure recurrence within 60 minutes from the start of therapy. Patients who failed the first treatment received a second and a third, if necessary. Patients did not receive randomized treatments after the first one, but the treating physician remained blinded. Treatment success: Lorazepam 64.9%, phenobarbital 58.2%, diazepam/phenytoin 55.8%, and phenytoin alone 43.6%. Using an “intention-to-treat” analysis, there was no statistical difference between the groups. Results of subsequent treatments in patients who failed the first therapy indicated that response rate significantly dropped regardless of treatment. Aggregate response rate to the second treatment was 7.0% and third treatment 2.3%.
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
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 alcohol abuse, personality disorders in the patient or the patient's parent(s).
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, and propylene glycol]
Solution, oral concentrate:
Lorazepam Intensol®: 2 mg/mL (30 mL) [alcohol free, dye free]
Tablet: 0.5 mg, 1 mg, 2 mg
Ativan®: 0.5 mg, 1 mg, 2 mg
Pricing: U.S. (www.drugstore.com)
Concentrate (Lorazepam Intensol)
2 mg/mL (30): $41.99
Tablets (Ativan)
0.5 mg (30): $64.38
1 mg (30): $74.99
2 mg (30): $117.29
Tablets (Lorazepam)
1 mg (30): $14.99
2 mg (30): $21.99
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International Brand Names
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