Pronunciation:

(lor A ze pam)

U.S. Brand Names:

Generic Available:

Canadian Brand Names:

Use:

Oral: Management of anxiety disorders or short-term relief of the symptoms of anxiety or anxiety associated with depressive symptoms

I.V.: Status epilepticus, preanesthesia for desired amnesia, antiemetic adjunct

Use - Unlabeled/Investigational:

Restrictions:

Pregnancy Risk Factor:

Pregnancy Implications:

Lactation:

Contraindications:

Warnings/Precautions:

The parenteral formulation of lorazepam contains polyethylene glycol and propylene glycol. Each agent has been associated with specific toxicities when administered in prolonged infusions at high dosages. Also contains benzyl alcohol - avoid rapid injection in neonates or prolonged infusions. Intra-arterial injection or extravasation should be avoided. Concurrent administration with scopolamine results in an increased risk of hallucinations, sedation, and irrational behavior.

Causes CNS depression (dose-related) resulting in sedation, dizziness, confusion, or ataxia which may impair physical and mental capabilities. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Use with caution in patients receiving other CNS depressants or psychoactive agents. Effects with other sedative drugs or ethanol may be potentiated. Benzodiazepines have been associated with falls and traumatic injury and should be used with extreme caution in patients who are at risk of these events (especially the elderly).

Lorazepam may cause anterograde amnesia. Paradoxical reactions, including hyperactive or aggressive behavior have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients. Does not have analgesic, antidepressant, or antipsychotic properties.

Use caution in patients with depression, particularly if suicidal risk may be present. Use with caution in patients with a history of drug dependence. Benzodiazepines have been associated with dependence and acute withdrawal symptoms on discontinuation or reduction in dose. Acute withdrawal, including seizures, may be precipitated after administration of flumazenil to patients receiving long-term benzodiazepine therapy.

As a hypnotic agent, 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.

Adverse Reactions:

>10%:

Central nervous system: Sedation

Respiratory: Respiratory depression

1% to 10%:

Cardiovascular: Hypotension

Central nervous system: Confusion, dizziness, akathisia, unsteadiness, headache, depression, disorientation, amnesia

Dermatologic: Dermatitis, rash

Gastrointestinal: Weight gain/loss, nausea, changes in appetite

Neuromuscular & skeletal: Weakness

Respiratory: Nasal congestion, hyperventilation, apnea

<1%: Blood dyscrasias, increased salivation, menstrual irregularities, physical and psychological dependence with prolonged use, reflex slowing, polyethylene glycol or propylene glycol poisoning (prolonged I.V. infusion)

Overdosage/Toxicology:

Drug Interactions:

CNS depressants: Sedative effects and/or respiratory depression may be additive with CNS depressants; includes ethanol, barbiturates, narcotic analgesics, and other sedative agents; monitor for increased effect

Levodopa: Lorazepam may decrease the antiparkinsonian efficacy of levodopa (limited documentation); monitor

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

Scopolamine: May increase the incidence of sedation, hallucinations, and irrational behavior; reported only with parenteral lorazepam

Theophylline: May partially antagonize some of the effects of benzodiazepines; monitor for decreased response; may require higher doses for sedation

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).

Stability:

I.V. is incompatible when administered in the same line with foscarnet, ondansetron, sargramostim

Infusion: Use 2 mg/mL injectable solution to prepare; dilute 1 mg/mL and mix in glass bottle; precipitation may develop; can also be administered undiluted via infusion

Compatibility:

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:

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

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

Excretion: Urine; feces (minimal)

Dosage:

Antiemetic:

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:

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)

Operative amnesia: Adults: I.V.: Up to 0.05 mg/kg (maximum: 4 mg/dose)

Sedation (preprocedure): Infants and Children:

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: 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 10-15 minutes if needed

Adolescents: 0.07 mg/kg slow I.V. over 2-5 minutes; maximum: 4 mg/dose; may repeat in 10-15 minutes

Adults: 4 mg/dose slow I.V. over 2-5 minutes; may repeat in 10-15 minutes; usual maximum dose: 8 mg

Rapid tranquilization of agitated patient (administer every 30-60 minutes):

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):

I.V.: 0.02-0.06 mg/kg every 2-6 hours

I.V. infusion: 0.01-0.1 mg/kg/hour

Administration:

I.M.: Should be administered deep into the muscle mass

I.V.: Do not exceed 2 mg/minute or 0.05 mg/kg over 2-5 minutes; dilute I.V. dose with equal volume of compatible diluent (D5W, NS, SWI); emergency resuscitative equipment should be available

Injection must be made slowly with repeated aspiration to make sure the injection is not intra-arterial and that perivascular extravasation has not occurred; inadvertent intra-arterial injection may produce arteriospasm resulting in gangrene which may require amputation

Monitoring Parameters:

Reference Range:

Patient Education:

Nursing Implications:

Additional Information:

Anesthesia and Critical Care Concerns/Other Considerations:

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 between 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.

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:

Dental Health: Effects on Dental Treatment:

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Oncology: Emetic Potential:

Oncology: Vesicant:

Dosage Forms:

Injection, solution (Ativan®): 2 mg/mL (1 mL, 10 mL); 4 mg/mL (1 mL, 10 mL) [contains benzyl alcohol]

Solution, oral concentrate (Lorazepam Intensol®): 2 mg/mL (30 mL) [alcohol free, dye free]

Tablet (Ativan®): 0.5 mg, 1 mg, 2 mg

International Brand Names: