General Administration Information
For storage information, see the specific product information within the How Supplied section.
Oral Solid Formulations
-When given in unequal doses, give the largest dose before bedtime.
Oral Liquid Formulations
Concentrated Oral Solution (2 mg/mL)
-Measure dosage using a calibrated oral syringe/dropper.
-Dilute the oral concentrate in water, juice, soda, or semi-solid food (e.g., applesauce, pudding) prior to administration. Administer immediately; do not store for future use.
-Storage: Protect from light. Store refrigerated at 36 to 46 degrees F. Discard opened bottle after 90 days.
Compounded Oral Suspension (1 mg/mL)
-Place 180 lorazepam 2 mg tablets in a 12-ounce amber glass bottle. Add the minimum volume of sterile water necessary for tablet dispersion. Shake the bottle until a slurry is formed. Add Ora-Plus and Ora-Sweet to bring the suspension to a concentration of 1 mg/mL (i.e., QS to a total volume of 360 mL). The volume of sterile water required will vary depending on the specific tablets used; this will also result in varying amounts of Ora-Plus and Ora-Sweet depending on the product.-In the chemical stability study, 2 different suspensions were made using the following ingredients:-180 lorazepam 2 mg tablets by Mylan Laboratories, 144 mL of sterile water, Ora-Plus 108 mL, and Ora-Sweet 83 mL.
-180 lorazepam 2 mg tablets by Watson Laboratories, 48 mL of sterile water, Ora-Plus 156 mL, and Ora-Sweet 146 mL.
-Each suspension was divided into 1 oz amber glass bottles for stability testing.
-Storage: Suspension is stable for 90 days when refrigerated (4 degrees C) or for 60 days at room temperature (22 degrees C).
-Avoid intra-arterial administration; arteriospasm can occur, which may cause tissue damage and/or gangrene.
-Only practitioners trained in maintaining a patent airway should administer lorazepam; have age- and size-appropriate resuscitative drugs and equipment readily available.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Dilute lorazepam with an equal volume of compatible diluent (0.9% Sodium Chloride Injection, 5% Dextrose Injection, or Sterile Water for Injection) immediately prior to use. Mix the contents thoroughly by gently inverting the syringe/vial repeatedly until a homogenous solution is obtained; do not shake vigorously.
-For neonatal doses: It may be necessary to make a less concentrated dilution to accurately measure the prescribed dose; some experts recommend dilution to limit the amount of benzyl alcohol administered (some products contain benzyl alcohol 20 mg/mL).-The following dilutions may be prepared using the 2 mg/mL concentration of lorazepam ONLY (do not use lorazepam 4 mg/mL to prepare; precipitation may occur) :-Lorazepam 0.2 mg/mL dilution: Add 1 mL of lorazepam (2 mg/mL) to 9 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection (benzyl alcohol content = 2 mg/mL if using a lorazepam product containing 2% benzyl alcohol).
-Lorazepam 0.5 mg/mL dilution: Add 1 mL of lorazepam (2 mg/mL) to 3 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection (benzyl alcohol content = 5 mg/mL if using a lorazepam product containing 2% benzyl alcohol).
-After dilution, inject directly into a vein or into the tubing of a freely-flowing compatible IV infusion. Direct IV injection should be made with repeated aspiration to ensure that none of the drug is injected intra-arterially and that perivascular extravasation does not occur.
-Inject slowly over 1 to 5 minutes; do not exceed 2 mg/minute.
-Storage: Lorazepam diluted with 5% Dextrose Injection or 0.9% Sodium Chloride Injection at a concentration of 0.2 mg/mL, 0.5 mg/mL, or 1 mg/mL is stable for 24 hours when stored in polypropylene syringes. Dilutions not prepared in a sterile environment should not be stored; discard immediately.
Continuous IV Infusion
NOTE: Lorazepam is not approved by the FDA for administration by continuous IV infusion.
-Use of glass or polyolefin containers is recommended; polypropylene syringes have also been used. Use of PVC containers results in significant drug loss; PVC administration sets can also be expected to contribute to sorption losses.
-Dilute lorazepam injection with a compatible diluent such as 5% Dextrose Injection (preferred) or 0.9% Sodium Chloride Injection to a final concentration of 0.2 mg/mL. For fluid restricted patients, data suggest that a concentration of 0.5 mg/mL or 1 mg/mL is stable for up to 24 hours and may be used.
-Lorazepam stability is very specific to the product used and is concentration dependent. Even at the recommended concentrations, precipitation has occurred in some situations. Carefully evaluate each syringe/bag before administration.
-Storage: Lorazepam diluted with 5% Dextrose Injection or 0.9% Sodium Chloride Injection at a concentration of 0.2 mg/mL, 0.5 mg/mL, or 1 mg/mL is stable for 24 hours when stored in polypropylene syringes or glass containers.
NOTE: For status epilepticus, IV administration is preferred over IM because therapeutic blood concentrations are reached more quickly with IV administration.
-When IV access is available, IV is the preferred route of administration due to injection site pain and slower onset associated with IM administration.
-When used as a premedication to produce lack of recall, IM lorazepam should be administered at least 2 hours before procedure.
-No dilution is needed.
-Inject deeply into a large muscle mass (e.g., anterolateral thigh or deltoid ).
Tolerance (or tachyphylaxis) may develop to the sedative effects of benzodiazepines, including lorazepam. If tolerance develops, clinicians should carefully assess the need for escalating doses. A temporary reduction in dosage may be beneficial in some cases to reverse the effects of tachyphylaxis.
Anterograde amnesia can occur after the administration of therapeutic doses of benzodiazepines, such as lorazepam. Amnesia and memory impairment are common pharmacologic effects and often clinically desirable with lorazepam use, particularly during critical care sedation, during the perioperative periods, or prior to or during certain medical procedures. The risk for developing anterograde amnesia increases at higher doses and with concurrent ingestion of alcohol.
Paradoxical central nervous system (CNS) excitation can occur with benzodiazepine use and is more common in pediatric patients compared to adults. In clinical study, paradoxical excitation occurred in 10%-30% of children < 8 years who were treated with lorazepam injection for status epilepticus; paradoxical excitation has also been reported in children who received lorazepam for other indications. Symptoms of paradoxical stimulation include hyperactivity, irritability, agitation, psychosis, hallucinations, delirium, hostility, aggression, rage, nightmares, talkativeness, excitement, mania, tremulousness, sleep disturbances, insomnia, increased muscle spasticity, anxiety, restlessness, crying/sobbing, euphoria, and hyperreflexia. If paradoxical reactions occur, it is recommended to continue parenteral lorazepam with caution; the manufacturer of oral lorazepam recommends discontinuation.
Central nervous system (CNS) adverse effects associated with lorazepam are common and many are dose-dependent. Drowsiness and sedation are the most common effects; although, these effects are often the therapeutic intent of the medication. CNS events occurring in clinical trials of parenteral lorazepam for the treatment of status epilepticus in adults include somnolence/drowsiness, headache, coma, stupor, brain edema, abnormal thinking, ataxia, confusion, myoclonus, and tremor. Confusion and depression have been reported in adult patients given parenteral lorazepam as a preanesthetic. Acute brain syndrome, nervousness, neuroleptic malignant syndrome, and muscle paralysis have been reported during post-marketing use of parenteral lorazepam. The most frequent adverse effects in adult patients with anxiety treated with oral lorazepam include drowsiness (15.9%), dizziness (6.9%), weakness (4.2%), and unsteadiness (3.4%). Confusion, disorientation, depression, unmasking of depression, disinhibition, suicidal ideation/attempt, ataxia, asthenia, extrapyramidal symptoms, tremor, vertigo, fatigue, and dysarthria were also reported. Tolerance may develop to CNS effects, including sedation and anxiolysis.
Nausea, vomiting, elevated hepatic enzymes, hypersalivation, and cystitis have been reported with parenteral use of lorazepam during adult clinical trials. In addition, constipation, appetite change, hyperbilirubinemia, and jaundice have been reported with oral lorazepam use. GI bleeding, liver damage, and urinary incontinence have been reported in post-marketing reports of parenteral lorazepam; however, a casual relationship to the drug has not been established. Because lorazepam oral concentrate contains polyethylene glycol and propylene glycol, high doses may result in osmotic diarrhea. If drug-induced diarrhea occurs, discontinue the oral concentrate and substitute the dose with lorazepam tablets. Although the clinical significance in humans is not known, esophageal dilation has occurred in rats with high doses (6 mg/kg/day) and prolonged therapy (> 1 year) of lorazepam. The effect was reversible only if therapy was stopped within 2 months of initial observation. Patients utilizing lorazepam for prolonged periods should have frequent evaluation for symptoms of upper GI disease.
Respiratory depression and related adverse effects are among the most concerning of lorazepam use. When used as monotherapy at typical doses, serious respiratory adverse events are not common; however, serious cardiorespiratory reactions, such as cardiac or respiratory arrest, have occurred and some have been fatal. During adult clinical trials of patients in status epilepticus, respiratory failure was one of the most common adverse events reported. Other respiratory effects reported include apnea, hyperventilation, hypoventilation, airway obstruction, and respiratory disorder. These effects may also occur with oral lorazepam therapy. Pulmonary edema, lung hemorrhage, pneumothorax, and pulmonary hypertension have been reported in post-marketing reports of parenteral lorazepam; however, a casual relationship to the drug has not been established. Worsening of obstructive pulmonary disease, including sleep apnea, has also been reported after lorazepam therapy. Respiratory complications are more likely to occur in critically ill patients, those with limited pulmonary reserve, or with concomitant use of other CNS depressants. Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately.
Cardiovascular adverse effects, particularly hypotension, may occur with lorazepam use; monitor the cardiac status of all patients receiving lorazepam. Although the incidence in children is not clear, hypotension was one of the most common adverse events reported in adult clinical trials of parenteral lorazepam for status epilepticus and has also been reported with oral lorazepam use. Hypotension is more likely to occur when lorazepam is used in combination with an opiate agonist or with medications that may lower blood pressure. In contrast, hypertension has also occasionally been observed during parenteral use. Arrhythmia, bradycardia, heart failure, heart block, pericardial effusion, and ventricular arrhythmia have been reported during post-marketing use of parenteral lorazepam. Although rare, cardiopulmonary arrest has also been reported. All patients receiving lorazepam should be monitored carefully for cardiac and/or respiratory adverse effects. Premature and low birth weight neonates, as well as any pediatric patient receiving high doses of lorazepam may be at particular risk for toxicities associated with benzyl alcohol, a preservative found in the parenteral solution, or propylene glycol and polyethylene glycol, additives found in both the parenteral and oral concentrate solutions. Symptoms of propylene glycol toxicity include diaphoresis, sinus tachycardia, acidosis, hyperosmolality, and central nervous system toxicity. Polyethylene glycol toxicity may result in acute tubular necrosis. In large amounts, benzyl alcohol may cause toxicity presenting as gasping respirations, acidosis, hypotension, bradycardia, and cardiovascular collapse.
Injection site reaction, including erythema and pain, can occur with the administration of parenteral lorazepam. Both intravenous and intramuscular administration may result in pain and erythema immediately after injection; patients receiving intramuscular lorazepam may also experience immediate burning at the injection site. In a small percentage of patients, adverse effects may present for > 24 hours. In addition, intra-arterial injection can produce arteriospasm that may result is significant tissue ischemia (e.g., gangrene); care must be taken to avoid intra-arterial administration.
Seizures and myoclonus/myoclonia have been reported after administration of parenteral lorazepam, especially in very low birth weight neonates. In addition, both pediatric and adult patients with atypical petit mal status epilepticus have developed brief tonic-clonic seizures shortly after lorazepam administration. Though seizures have been reported with both parenteral and oral use of lorazepam, the incidence is thought to be rare. The susceptibility of neonates to these central nervous system (CNS) events may be multifactorial; some experts suggest the sensitivity may be due to pharmacokinetic and mechanistic differences in the neonatal population, while others speculate additives in the parenteral and oral concentrate formulations may sensitize this population to such effects. Symptoms of benzyl alcohol and propylene glycol toxicity include central nervous effects such as seizures and intraventricular hemorrhage.
Prolonged use of lorazepam can produce physiological dependence with or without psychological dependence. While physiological and psychological dependence as a result of abuse is a concern with all benzodiazepines, lorazepam dependence in pediatric patients is more likely to occur in the setting of prolonged infusions in critically ill patients or chronic therapy. The optimal weaning schedule has not been determined; however, it is clear that patients who receive prolonged infusions or chronic therapy should be gradually weaned from the drug to avoid withdrawal. Withdrawal symptoms may include convulsions, hallucinations, tremor, abdominal and muscle cramps, vomiting, and sweating. Withdrawal symptoms in infants may include abdominal distention and tachycardia.
Metabolic acidosis has occurred in patients receiving parenteral lorazepam in clinical trials for the treatment of status epilepticus. SIADH, hyponatremia, thrombocytopenia, coagulation disorder (coagulopathy), agranulocytosis, pancytopenia, have been reported during lorazepam therapy; however, the causality to the drug is not established. In addition to adverse effects from lorazepam, additives in the parenteral and oral concentrate solutions (e.g., benzyl alcohol, propylene glycol, polyethylene glycol) may cause metabolic abnormalities when the drug is used at higher than recommended doses, for a prolonged period of time, or in the presence of renal impairment. Benzyl alcohol toxicity may present with metabolic acidosis, while propylene glycol toxicity may present with lactic acidosis and hyperosmolality. In patients receiving parenteral lorazepam, monitor for metabolic and lactic acidosis; particular attention should be given to neonates and patients with renal impairment.
Infection and chills have been reported in patients receiving parenteral lorazepam during clinical trials. In addition, hypothermia and autonomic manifestations have been associated with oral lorazepam use.
Hypersensitivity reactions, anaphylactoid reactions, dermatological symptoms, allergic skin reactions, and alopecia have been reported during lorazepam therapy. Skin rash (unspecified) has been reported with parenteral use.
Diplopia and blurred vision have been reported with lorazepam use. In addition, adult patients receiving parenteral lorazepam as a preanesthetic infrequently reported depressed hearing (hearing loss) during clinical trials.
Lorazepam is contraindicated in any patient with a known or suspected benzodiazepine hypersensitivity. Lorazepam injection is contraindicated in patients who are hypersensitive to other ingredients in these products; both the oral and injectable solutions contain propylene glycol and polyethylene glycol. Lorazepam injection also contains benzyl alcohol as a preservative and is contraindicated in premature neonates and in any patient with known or suspected benzyl alcohol hypersensitivity. Pediatric patients, in particular premature neonates and term neonates may be more sensitive to these compounds. Although normal therapeutic doses of lorazepam contain very small amounts of propylene glycol, polyethylene glycol, and benzyl alcohol, the clinician should be aware of the toxic potential, especially if other drugs containing the compounds are administered. Excessive propylene glycol can cause lactic acidosis, hyperosmolality, tachypnea, tachycardia, diaphoresis, and central nervous system toxicity (e.g., seizures, intraventricular hemorrhage). Excessive amounts of benzyl alcohol in neonates have been associated with hypotension, metabolic acidosis, and kernicterus. A "gasping syndrome" characterized by CNS depression, metabolic acidosis, and gasping respirations has been associated with benzyl alcohol dosages more than 99 mg/kg/day in neonates. However, the minimum amount of benzyl alcohol at which toxicity may occur is unknown and premature and low-birth-weight neonates may be more likely to develop toxicity. Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in pediatric patients younger than 3 years, including in utero exposure during the third trimester, may have negative effects on brain development. Consider the benefits of appropriate anesthesia in a young child against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required during the first 3 years of life. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development. Intraarterial administration of lorazepam is contraindicated; providers should take caution to make sure perivascular extravasation does not occur.
As with other benzodiazepines, lorazepam should be used with extreme caution in patients with pulmonary disease and in patients with respiratory insufficiency resulting from chronic lung disease (CLD), status asthmaticus, abnormal airway anatomy, cyanotic congenital heart disease, or pulmonary hypertension. Additionally, avoid coadministration with other CNS depressants, especially opioids, when possible, as this significantly increases the risk for profound sedation, respiratory depression, low blood pressure, and death. Reserve concomitant use of these drugs for patients in whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations possible and monitor patients closely for signs and symptoms of respiratory depression and sedation. Lorazepam injection is contraindicated in patients with sleep apnea syndrome or severe respiratory insufficiency who are not receiving mechanical ventilation. Lorazepam can cause respiratory depression, apnea, airway obstruction, and oxygen desaturation; it is more likely to cause adverse respiratory effects when administered to patients with pulmonary conditions, significant CNS depression, or ethanol intoxication. In addition, hypercarbia and hypoxia can occur after lorazepam administration and may pose a significant risk to patients with congenital heart disease or pulmonary hypertension. Carefully monitor respiratory status and oxygen saturation in at risk patients.
Particular caution is required in determining the amount of time needed after outpatient procedures or surgery before it is safe for any patient to participate safely in ambulation or activities requiring coordination and concentration (e.g., riding a bicycle). Although recommendations specific to pediatric patients are not available, FDA-approved product labeling of lorazepam recommends that no patient get out of bed unassisted within 8 hours of lorazepam injection. In addition, it is recommended that patients not drive a motor vehicle until 24 to 48 hours after surgery or until the central nervous system depressant effects have subsided, whichever is longer. The caregivers of ambulatory patients on oral therapy should be cautioned to monitor the patient carefully until it is clear how lorazepam may affect the patient.
Lorazepam is metabolized in the liver and primarily excreted by the kidneys; use with caution in patients with hepatic disease and/or renal impairment. As with all benzodiazepines, the use of lorazepam may worsen hepatic encephalopathy and should be used with extreme caution in patients with severe hepatic insufficiency. Because lorazepam undergoes conjugative metabolism as opposed to oxidative metabolism, it is relatively safer to use in patients with hepatic dysfunction with careful monitoring versus other benzodiazepines. Half-life may be prolonged in patients with renal impairment or renal failure. In addition, propylene glycol and polyethylene glycol toxicity may be more likely to develop in patients with renal impairment.
Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in neonates, infants, and children younger than 3 years, including in utero exposure during the third trimester, may have negative effects on brain development. Consider the benefits of appropriate anesthesia in young children against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required during the first 3 years of life. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development. Chronic in utero exposure to lorazepam may lead to signs and symptoms of drug withdrawal in neonates after birth. Monitor the exposed neonate for withdrawal symptoms including irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight loss, and failure to gain weight. If symptoms are severe, pharmacologic therapy may be necessary.
Lorazepam can cause physical and psychological dependence and should be used with extreme caution in patients with known, suspected, or a history of substance abuse. Benzodiazepine dependence can occur after administration of therapeutic doses for as few as 1 to 2 weeks. Generally, benzodiazepines should be prescribed for short periods (2 to 4 weeks) with continued reevaluation of the need for treatment. Abrupt discontinuation of lorazepam after prolonged use can cause seizures in susceptible patients. Abrupt discontinuation of benzodiazepine therapy has been reported to cause withdrawal symptoms including convulsions, hallucinations, tremor, abdominal and muscle cramps, vomiting, and sweating. Withdrawal symptoms in infants may include abdominal distention and tachycardia. Benzodiazepine withdrawal is more likely to occur after abrupt cessation after excessive or prolonged doses. Discontinue benzodiazepines cautiously and slowly, using a very gradual dosage-tapering schedule.
According to the FDA-approved labeling, lorazepam is contraindicated in patients with acute closed-angle glaucoma. Lorazepam may be used in patients with open-angle glaucoma who are receiving appropriate treatment. The mechanistic rational for this contraindication has been questioned, as benzodiazepines do not have antimuscarinic activity and do not raise intraocular pressure.
Lorazepam is not recommended for use in patients with primary depressive disorder, as preexisting depression may emerge or worsen during the use of benzodiazepines. If lorazepam is used in patients with depression, ensure adequate antidepressant therapy and monitor closely for worsening symptoms. Administer lorazepam cautiously to patients with a history of suicidal ideation; do not prescribe large quantities for patients with known suicidal ideation or a history of suicide attempt. Though FDA-approved oral product labeling specifically recommends against the use of lorazepam in psychosis, benzodiazepines are commonly used in clinical practice for the acute management of psychosis and mania, as well as in the treatment of extrapyramidal symptoms associated with antipsychotics. Benzodiazepines may cause disinhibition and paradoxical stimulation (e.g., agitation, mania), both of which are more common in children. In addition, paradoxical reactions are more common in patients with psychiatric and/or personality disorders, particularly in patients with histories of anger and aggression. Hence, benzodiazepines should be used with caution in patients with a history of autism, bipolar disorder, or psychosis.
Description: Lorazepam is an intermediate-acting benzodiazepine used for sedation, anxiolysis, and amnesia. Lorazepam is also used as an adjunct to antiemetic therapy. Intravenous lorazepam is used off-label for sedation and management of agitation in mechanically ventilated patients and as an initial therapy to treat status epilepticus. Historically, many experts have advocated the use of lorazepam over diazepam for status epilepticus based on proposed potential advantages (e.g., greater efficacy, lower incidence of respiratory depression, longer duration of effect). However, no significant difference in efficacy and tolerability has been demonstrated. In a large multicenter, double-blind, randomized clinical trial involving 273 pediatric patients, cessation of status epilepticus occurred in 72.9% and 72.1% of lorazepam- and diazepam-treated patients, respectively (absolute efficacy difference, 0.8%; 95% CI, -11.4% to 9.8%). Both agents had rates of severe respiratory depression of less than 20% (16% of those given diazepam and 18% of those given lorazepam required assisted ventilation; absolute risk difference, 1.6%; 95% CI, -9.9% to 6.8%). There were no statistically significant differences in secondary outcomes (e.g., response latency, need for a second dose of study medication, need for additional anticonvulsant medications, sustained absence of seizures) with the exception of the incidence of sedation, which was more prevalent in the lorazepam group (67% vs. 50%; absolute risk difference, 16.9%; 95% CI 6.1% to 27.7%) and the return to baseline mental status which was approximately 2 hours longer in the lorazepam group. In the critical care population, midazolam is often the preferred agent for sedation and amnesia in pediatrics, although lorazepam may be used as an alternative. Lorazepam is not metabolized to active metabolites; because of its metabolic pathway, the pharmacokinetics are less likely than other benzodiazepines to be altered in the presence of hepatic dysfunction. Lorazepam parenteral injection contains benzyl alcohol, and both the injection and oral concentrate solution contain propylene glycol and polyethylene glycol as additives; these additives may be toxic in neonates, when used at higher than recommended doses, and/or after prolonged infusions. Oral lorazepam is FDA-approved in pediatric patients as young as 12 years; parenteral lorazepam is not FDA-approved for pediatric use but is used off-label in patients as young as neonates.
For the treatment of status epilepticus*:
Intravenous (preferred) or Intramuscular dosage:
IV administration is preferred because therapeutic concentrations are not reached as quickly with IM administration; however, if IV access is not available, IM administration may be useful.
Neonates: 0.05 to 0.1 mg/kg IV or IM as a single dose given over 2 to 5 minutes; may repeat once in 10 to 15 minutes if needed.
Infants, Children, and Adolescents: 0.05 to 0.1 mg/kg IV or IM (Max: 4 mg) as a single dose given over 1 to 2 minutes (Max rate: 2 mg/minute); may repeat once in 5 to 15 minutes if needed.
For the short-term management of anxiety:
Children younger than 12 years*: Dosage not available for anxiety disorders; however, lorazepam 0.025 to 0.05 mg/kg/dose PO as needed (no more frequently than every 4 hours) has been used in burn patients with anxiety related to being in the hospital, dressing changes, etc. In pediatric patients 12 years and older, the daily dosage for anxiety disorders is typically divided into 2 to 3 doses and should not exceed 10 mg/day.
Children and Adolescents 12 to 17 years: 2 to 3 mg/day PO given in 2 to 3 divided doses initially; titrate dosage gradually as needed. The usual dosage is 2 to 6 mg/day but may vary from 1 to 10 mg/day. When higher dosage is needed, the evening dose should be increased before the daytime doses. Efficacy of long-term use (more than 4 months) for anxiety disorders has not been evaluated.
For procedural sedation* and amnesia induction* and to control preoperative anxiety:
Infants, Children, and Adolescents: 0.05 mg/kg PO as a single dose (Max: 4 mg) 45 to 90 minutes prior to procedure. Dose range: 0.02 to 0.09 mg/kg/dose.
Intravenous or Intramuscular dosage:
Infants, Children, and Adolescents: 0.05 to 0.1 mg/kg IV or IM as a single dose (Max: 2 to 4 mg). Dose range: 0.02 to 0.1 mg/kg/dose. For optimum lack of recall, administer IV dose 15 to 20 minutes prior to procedure and IM dose 2 hours prior to procedure.
For sedation maintenance* in mechanically-ventilated patients:
Intermittent Intravenous dosage:
Neonates: 0.05 mg/kg/dose IV every 2 to 8 hours as needed. Dose range: 0.025 to 0.1 mg/kg/dose. Due to a prolonged half-life, neonates may require doses at less frequent intervals (e.g., every 6 to 8 hours) compared to children and adolescents.
Infants, Children, and Adolescents: 0.05 mg/kg/dose IV every 2 to 8 hours as needed (Max initial dose: 2 mg). Dose range: 0.025 to 0.1 mg/kg/dose. Due to a prolonged half-life, infants may require doses at less frequent intervals (e.g., every 6 to 8 hours) compared to children and adolescents.
Continuous IV Infusion dosage*:
Neonates: Safety and efficacy have not been established; due to a long duration of action in neonates and the presence of benzyl alcohol in the parenteral formulation, intermittent dosing is preferred in order to avoid drug accumulation and toxicity.
Infants, Children, and Adolescents: Limited published data are available in the pediatric population. An initial infusion rate of 0.025 to 0.05 mg/kg/hour IV is recommended by some experts. Max initial rate: 2 mg/hour. A published sedation protocol for pediatric mechanically ventilated patients recommends an initial infusion rate of 0.01 mg/kg/hour IV. If 3 intermittent boluses of lorazepam are needed in a 6 hour time period, increase the infusion rate by 0.005 mg/kg/hour (50% of initial rate). If no additional boluses are needed, consider reducing the infusion rate. Titrate to desired level of sedation. High doses and prolonged infusions may increase the risk of propylene glycol toxicity; monitor patients carefully.
For chemotherapy-induced nausea/vomiting prophylaxis* as an adjunct to antiemetics:
Children and Adolescents: Limited data available; 0.025 to 0.05 mg/kg/dose PO every 6 hours as needed for management of anticipatory nausea/vomiting. Max: 4 mg/dose. May start 12 to 24 hours prior to chemotherapy.
Children and Adolescents: 0.04 to 0.05 mg/kg IV as a single dose administered 30 minutes prior to chemotherapy. Infuse over 15 to 20 minutes. Max: 4 mg/dose. Alternatively, 0.025 to 0.05 mg/kg/dose IV every 6 hours as needed for management of anticipatory or breakthrough nausea/vomiting. Max: 4 mg/dose.
For the short-term treatment of insomnia due to anxiety or transient situational stress:
Children and Adolescents 12 to 17 years: 2 to 4 mg PO at bedtime as needed. Efficacy of long-term use (more than 4 months) has not been evaluated.
For the treatment of acute agitation*:
Children and Adolescents: 0.05 to 0.1 mg/kg/dose PO every 30 to 60 minutes as needed (Max: 2 mg). Onset of action occurs in 20 to 30 minutes, peaks at 2 hours, and persists 6 to 8 hours.
Children and Adolescents: 0.05 to 0.1 mg/kg/dose IM every 30 to 60 minutes as needed (Max: 2 mg). Onset of action occurs in 15 minutes, peaks at 1 hour, and persists 6 to 8 hours.
Children and Adolescents: 0.05 to 0.1 mg/kg/dose IV every 30 to 60 minutes as needed (Max: 2 mg). Onset of action occurs in 5 to 10 minutes, peaks at 30 minutes, and persists 2 hours.
Maximum Dosage Limits:
Safety and efficacy have not been established. Specific maximum dosage information not available; the dose required is dependent on route of administration, indication, and clinical response.
Safety and efficacy have not been established. Specific maximum dosage information not available; the dose required is dependent on route of administration, indication, and clinical response.
1 to 11 years: Safety and efficacy have not been established. Specific maximum dosage information not available; the dose required is dependent on route of administration, indication, and clinical response.
12 years: 10 mg/day PO for anxiety disorders; 4 mg/day PO for insomnia. Safety and efficacy of parenteral lorazepam have not been established. Specific maximum dosage information not available; the dose required is dependent on route of administration, indication, and clinical response.
10 mg/day PO for anxiety disorders; 4 mg/day PO for insomnia. Safety and efficacy of parenteral lorazepam have not been established. Specific maximum dosage information not available; the dose required is dependent on route of administration, indication, and clinical response.
Patients with Hepatic Impairment Dosing
Lorazepam dosage should be modified based on clinical response and degree of hepatic impairment; a smaller dosage may be sufficient for patients with severe insufficiency. No quantitative recommendations are available.
Patients with Renal Impairment Dosing
Lorazepam dosage should be modified depending on clinical response and degree of renal impairment. No quantitative recommendations are available. Patients with renal impairment receiving high doses of intravenous lorazepam may be more likely to develop propylene glycol toxicity.
Monograph content under development
Mechanism of Action: Benzodiazepines act at the level of the limbic, thalamic, and hypothalamic regions of the central nervous system (CNS) and can produce any level of CNS depression required including sedation, hypnosis, skeletal muscle relaxation, and anticonvulsant activity. Benzodiazepines exert their effects through enhancement of the gamma-aminobutyric acid (GABA)-benzodiazepine complex. GABA is an inhibitory neurotransmitter that exerts its effects at specific receptor subtypes designated GABA-A and GABA-B. GABA-A is the primary receptor subtype in the CNS and is thought to be involved in the actions of anxiolytics and sedatives.
Specific benzodiazepine receptor subtypes are thought to be coupled to GABA-A receptors. Three types of BNZ receptors are located in the CNS and other tissues; the BNZ1 receptors are located in the cerebellum and cerebral cortex, the BNZ2 receptors in the cerebral cortex and spinal cord, and the BNZ3 receptors in peripheral tissues. Activation of the BNZ1 receptor is thought to mediate sleep while the BNZ2 receptor affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. Benzodiazepines bind nonspecifically to BNZ1 and BNZ2, which ultimately enhances the effects of GABA. Lorazepam exhibits highly specific affinity for its recognition site. Unlike barbiturates, which augment GABA responses by increasing the length of time that chloride channels are open, benzodiazepines enhance the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.
The antianxiety action of benzodiazepines may be a result of their ability to block cortical and limbic arousal after stimulation of the reticular pathways while muscle relaxation properties are mediated by inhibiting both mono- and polysynaptic pathways. Benzodiazepine can also depress muscle and motor nerve function directly. Animal studies of the anticonvulsant actions suggest that benzodiazepines augment presynaptic inhibition of neurons, thereby limiting the spread of electrical activity, although they do not actually inhibit the abnormally discharging focus.
As an anticonvulsant used acutely for seizure activity, lorazepam is preferred over diazepam because it is a less lipophilic agent. Although it has a slower onset of action, lorazepam persists in the CNS longer than diazepam.
Pharmacokinetics: Lorazepam is administered orally and parenterally. The drug has also been given sublingually; although, specific sublingual dosage forms are not available in the United States. Lorazepam is lipophilic; it is widely distributed and crosses the blood-brain barrier. It is approximately 85% to 90% protein-bound. In healthy adults, the mean volume of distribution (Vd) is 1.3 L/kg; the Vd is smaller in neonates and slightly larger in non-neonatal pediatric patients. Lorazepam is conjugated by the liver to lorazepam glucuronide, an inactive metabolite. In healthy adults, mean plasma clearance is 1.1 mL/kg/minute, and elimination half-life is 12 to 14 hours (range 9 to 22 hours). Lorazepam clearance is significantly slower in neonates compared to adults; clearance in older children is dependent on the specific population and varies from slightly slower to slightly faster than that of adults. Lorazepam is excreted in the urine primarily as the inactive glucuronide metabolite; lorazepam also undergoes enterohepatic recirculation.
Affected cytochrome P450 isoenzymes: none
Lorazepam is readily absorbed with a bioavailability of 90% (both tablets and solution). Subjective central nervous system effects occur within 1 to 2 hours. After administration of a 2 mg dose in adult patients, peak concentrations of approximately 20 ng/mL occur in approximately 2 hours. Plasma concentrations are proportional to the dose given.
Optimum anxiolytic and sedative effects occur within 15 to 20 minutes after administration; however, onset of effect occurs more rapidly. The degree of sedation is dependent on the dose administered and the presence or absence of other medications. When used as an anticonvulsant, cessation of seizure activity may occur within 5 minutes. After IV administration of a 4 mg dose to adult patients, initial concentrations are approximately 70 ng/mL. Plasma concentrations are proportional to the dose given. Based on non-neonatal pediatric pharmacokinetic models, lorazepam 0.1 mg/kg (up to 4 mg) is expected to achieve a Cmax of 100 ng/mL; concentrations more than 30 ng/mL are expected to be maintained for 6 to 12 hours for most pediatric patients. After the initial dose, a second dose of 0.05 mg/kg (up to 2 mg) is expected to maintain a typically desired concentration for seizure suppression (more than 50 ng/mL) for approximately 12 hours. Duration of the sedative effect is approximately 6 to 12 hours for most patients.
Lorazepam is absorbed rapidly and completely after intramuscular injection with a bioavailability more than 90%. Optimum anxiolytic and sedative effects occur approximately 1 to 2 hours after administration, with the degree of sedation dependent on the dose administered and the presence or absence of other medications. After administration of 4 mg IM to adult patients, peak concentrations of approximately 48 ng/mL are reached within 3 hours.
Neonates have significantly longer half-lives and slower clearance than other populations. The mean plasma clearance and elimination half-life of a single dose of IV lorazepam (0.05 to 0.1 mg/kg) in 10 term neonates (gestational age 37 to 41 weeks) with asphyxia neonatorum presenting with seizures in the first 48 hours of life was 0.232 mL/kg/minute and 40.2 hours (range 18 to 73 hours), respectively. These values are most likely affected by altered protein binding and decreased hepatic enzyme activity in neonates. Volume of distribution (Vd) was 0.76 L/kg (range 0.14 to 1.3 L/kg); this smaller Vd compared to adults is consistent with the lower percentage of adipose tissue in the neonatal population.
Infants, Children, and Adolescents
Infants, children, and adolescents have slightly longer half-lives and larger volume of distribution (Vd) compared to adults. In a study of children and adolescents 2 years and older with acute lymphocytic leukemia, the mean Vd was 50% higher than that of healthy adults. Mean half-life was 30% longer in children and 2-fold greater in adolescents. In a pharmacokinetic study of 63 patients aged 5 months to 17 years, mean plasma clearance (CL) and elimination half-life (t1/2) of IV lorazepam (0.05 to 0.1 mg/kg/dose) was 1.2 mL/kg/minute and 16.8 hours (range 6 to 42 hours), respectively. Mean volume of distribution was 1.48 L/kg. In general, Vd and CL decreased, and t1/2 increased with ascending age. Reported data is as follows: for infants and children 5 months to 2 years, Vd = 1.62 L/kg, t1/2 = 15.8 hours, CL = 1.57 mL/kg/minute; for children 3 to 12 years, Vd = 1.5 L/kg, t1/2 = 16.9 hours, CL = 1.12 mL/kg/minute; for adolescents 13 to 18 years: Vd = 1.27 L/kg, t1/2 = 17.8 hours, CL = 0.95 mL/kg/minute.
Because lorazepam undergoes conjugative metabolism as opposed to oxidative metabolism, the pharmacokinetics of the drug are less likely to be altered in the presence of hepatic dysfunction compared to many other benzodiazepines. Liver disease is not expected to have a clinically significant effect on lorazepam clearance.
Renal impairment is expected to decrease the elimination of lorazepam glucuronide, but there should be no direct effect on the conversion of lorazepam to lorazepam glucuronide (i.e., inactivation of lorazepam). In 6 adults with renal impairment (CrCl 22 +/- 9 mL/minute), the mean Vd and terminal elimination half-life were 40% and 25% higher, respectively, compared to those of healthy adults. However, the mean total clearance did not change.
In 4 adults receiving chronic hemodialysis, the mean Vd and terminal elimination half-life were 75% higher compared to those of healthy adults; however, the mean total clearance was not different. During a 6-hour dialysis session, 8% of the administered dose was removed as intact lorazepam and 40% of the administered dose was removed as lorazepam glucuronide.