LORAZEPAM INTENSOL

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
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.

Extemporaneous Compounding-Oral
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).



Injectable Administration
-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.
Intravenous Administration
IV Push
-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.

Intramuscular Administration
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 [children and adolescents only]).

Anterograde amnesia can occur after the administration of therapeutic doses of benzodiazepines, such as lorazepam. Amnesia and memory impairment are clinically desirable during critical care sedation, 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 than adults and in patients with a psychiatric disorder. In a clinical study, paradoxical excitation occurred in 10% to 30% of children less than 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, further use of parenteral lorazepam should be considered 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 pre-anesthetic. Acute brain syndrome, nervousness, neuroleptic malignant syndrome-like symptoms, and muscle paralysis have been reported during postmarketing use of parenteral lorazepam. Myoclonus has particularly been associated with lorazepam injection use in very low birth weight neonates. 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, dysarthria, and autonomic manifestations were also reported. Tolerance may develop to CNS effects, such as sedation. CNS depression may be severe and result in profound sedation, along with depressed respiration, and may occasionally result in death. Fatalities have occurred when benzodiazepines are coadministered with opioid medications and/or alcohol.

Nausea, vomiting, elevated hepatic enzymes, and hypersalivation 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 and liver damage have been reported during postmarketing use of parenteral lorazepam. 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. Urinary incontinence has been reported during postmarketing use of parenteral lorazepam; however, a casual relationship to the drug has not been established.

Respiratory depression may occur during benzodiazepine therapy, occasionally resulting in death. Respiratory depression, sometimes fatal, has occurred when benzodiazepines are coadministered with opioid medications and/or alcohol. 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 postmarketing 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.

Hypotension and cardiac arrest have been reported following parenteral administration of benzodiazepines to severely ill patients or to patients with compromised respiratory function. Monitor the cardiac status of all patients receiving parenteral lorazepam. Although the incidence of hypotension 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. Hypertension has occasionally been observed during parenteral use. Ventricular arrhythmias, bradycardia, heart failure, AV block, pericardial effusion, and sinus tachycardia have been reported during postmarketing use of parenteral lorazepam. 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 more than 24 hours. In addition, intra-arterial injection can produce arteriospasm that may result in significant tissue ischemia (e.g., gangrene); therefore, this route of administration is contraindicated.

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 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. Although uncommon, seizures may occur following the discontinuation of benzodiazepine therapy.

Hypersensitivity reactions, anaphylactoid reactions, dermatological symptoms, allergic skin reactions, and alopecia have been reported during lorazepam therapy. Skin rash 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.

Metabolic acidosis has occurred in patients receiving parenteral lorazepam in clinical trials for the treatment of status epilepticus. Additives in the parenteral (e.g., benzyl alcohol, propylene glycol, polyethylene glycol) and oral concentrate solution (e.g., polyethylene glycol, propylene 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, propylene glycol toxicity may present with lactic acidosis and hyperosmolality, and polyethylene glycol toxicity may be associated with renal tubular necrosis. In patients receiving parenteral lorazepam, monitor for metabolic and lactic acidosis; particular attention should be given to neonates and patients with renal impairment. SIADH and hyponatremia have been reported during lorazepam therapy; however, causality to the drug is not established.

Thrombocytopenia, agranulocytosis, leukopenia, pancytopenia, and elevated LDH have been reported with lorazepam use. Coagulopathy has been reported during postmarketing use of injectable lorazepam; however, causality to the drug has not been established.

Infection, chills, and cystitis were reported in less than 1% of patients receiving parenteral lorazepam during clinical trials for status epilepticus. Hypothermia has been reported during treatment with oral lorazepam. Aggravation of pheochromocytoma has been reported during postmarketing use of injectable lorazepam; however, causality to the drug has not been established.

Tolerance to lorazepam may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of lorazepam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

Prolonged use of benzodiazepines can produce physiological dependence with or without psychological dependence. The risk of psychological dependence increases in those with a history of alcohol or substance abuse. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, and death. Caution is advised when considering the use of benzodiazepines in patients with a known or suspected history of substance abuse. To discourage abuse, prescribe the smallest appropriate quantity of the benzodiazepine and provide proper disposal instructions for unused drug. Avoid or minimize concomitant use of CNS depressants or other medications associated with addiction or abuse. Clinically significant physiological dependence may occur with continued use of benzodiazepines. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of benzodiazepines after continued use may precipitate acute withdrawal reactions, which can be life-threatening. 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 range from mild dysphoria and insomnia to a major withdrawal syndrome including abdominal and muscle cramps, vomiting, sweating, tremors, and seizures. Withdrawal symptoms in infants may include abdominal distention and tachycardia. In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Use a gradual dosage taper to lower the risk of withdrawal reactions when reducing the dose or discontinuing therapy.

Benzodiazepines cross the placenta and may produce sedation, hypotonia, lethargy, and neonatal respiratory depression at birth. Monitor neonates exposed during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Neonatal withdrawal or a neonatal abstinence syndrome has also been reported following the ingestion of therapeutic doses of benzodiazepines during the last weeks of pregnancy. Clinical manifestations of neonatal withdrawal may include hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties. These complications can appear shortly after delivery to 3 weeks after birth and persist from hours to several months, depending on the degree of dependence and pharmacokinetic profile of the benzodiazepine. Observe neonates who are exposed to benzodiazepines in utero during the later stages of pregnancy for symptoms of withdrawal and manage appropriately. Benzodiazepines should be withdrawn cautiously and slowly, using a very gradual dosage-tapering schedule.

Lorazepam is contraindicated in patients with a benzodiazepine hypersensitivity or a hypersensitivity to any component of the formulation. Lorazepam injection is contraindicated in those with polyethylene glycol, propylene glycol, and/or benzyl alcohol hypersensitivity due to these components in the injection formulation. Lorazepam oral solution concentrate also contains polyethylene glycol and propylene glycol. Because lorazepam injection contains benzyl alcohol as a preservative, it is contraindicated in premature neonates. 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. Pediatric patients, in particular premature neonates and term neonates are more sensitive to these compounds. 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. The lorazepam extended-release 1 mg capsules contain tartrazine (FD and C Yellow No. 5), which may cause allergic-type reactions in patients with tartrazine dye hypersensitivity.

As with other benzodiazepines, lorazepam causes CNS depression that may lead to respiratory effects and should be used with extreme caution in pediatric patients with significant pulmonary disease such as respiratory insufficiency resulting from chronic lung disease (CLD) or sleep apnea. Lorazepam injection is contraindicated in patients with sleep apnea syndrome or severe respiratory insufficiency who are not receiving mechanical ventilation. 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. In addition, hypercarbia and hypoxia can occur after lorazepam administration. 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). The CNS depressant effects of benzodiazepines are additive to ethanol ingestion or other CNS depressants. Caution against use of alcohol during treatment with benzodiazepines. Use, particularly in the setting of ethanol intoxication, may cause marked CNS and respiratory depression and risk for death. 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. In utero exposure to benzodiazepines during the later stages of pregnancy may result in decreased fetal movement and/or heart rate variability, sedation (hypotonia, lethargy, neonatal respiratory depression), neonatal abstinence syndrome (NAS), floppy infant syndrome (FIS), or other withdrawal symptoms during the postnatal period. Monitor the neonate for hypotonia and withdrawal symptoms, including hyperreflexia, irritability, restlessness, tremors, inconsolable crying, or feeding difficulties and manage accordingly. The incidence, time to onset, and duration of NAS or FIS symptoms is multi-factorial (e.g., duration of use, drug lipophilicity, placental disposition, degree of accumulation in neonatal tissues). FIS typically occurs after chronic fetal exposure to long-acting benzodiazepines, or when benzodiazepines are administered shortly before delivery, resulting in newborn toxicity of variable severity and duration. FIS primarily occurs within the first few hours after labor and may last for up to 14 days.

Use lorazepam with caution in patients with a history of alcoholism or substance abuse due to the potential for psychological dependence. The use of benzodiazepines exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive benzodiazepines routinely for development of these behaviors or conditions. A potential risk of abuse should not preclude appropriate treatment in any patient, but requires more intensive counseling and monitoring. To discourage abuse, the smallest appropriate quantity of the benzodiazepine should be prescribed, and proper disposal instructions for unused drug should be given to patients. Avoid or minimize concomitant use of CNS depressants or other medications associated with addiction or abuse. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, and death. Advise patients to seek immediate medical attention if they experience symptoms such as trouble breathing. Abrupt discontinuation or rapid dosage reduction of benzodiazepines after continued use may precipitate acute withdrawal reactions, which can be life-threatening. The risks of physiological dependence and withdrawal increase with longer treatment duration and higher daily dose. Benzodiazepine dependence can occur after administration of therapeutic doses for as few as 1 to 2 weeks and withdrawal symptoms may be seen after the discontinuation of therapy. To reduce the risk of acute withdrawal reactions, use a gradual taper to reduce the dosage or to discontinue benzodiazepines. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently, decrease the dosage more slowly. Patients with a history of a seizure disorder should not be withdrawn abruptly from benzodiazepines due to the risk of precipitating seizures; status epilepticus has also been reported. Clinicians should be aware that the use of flumazenil may increase the risk of seizures, particularly in long-term users of benzodiazepines. 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.

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.

During the treatment of status epilepticus, the use of injectable benzodiazepines, like lorazepam, is often implemented as an adjunct to other supportive therapies. In status epilepticus, ventilatory support and other life-saving measures should be readily available. Additional seizure maintenance medication should be ordered if required. The sedative effects of injectable benzodiazepines may add to the CNS depressive state seen in the postictal stage. Ventilatory support should also be available for the preanesthetic use of injectable benzodiazepines.

Description: Lorazepam is an intermediate-acting benzodiazepine used for sedation, anxiolysis, amnesia, and as an adjunct to antiemetic therapy. Oral lorazepam is approved in children and adolescents 12 years and older for the short-term treatment of anxiety or insomnia due to anxiety or transient situational stress. Intravenous lorazepam is used off-label for sedation and management of agitation in mechanically ventilated patients and has been used in patients as young as neonates. According to the National Institute for Health and Care Excellence (NICE) guidelines for treating status epilepticus in children, intravenous lorazepam is recommended as a first-line treatment option if IV access can be established in an appropriate setting. 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. Because lorazepam is not metabolized to active metabolites, it is a preferred benzodiazepine in the presence of hepatic dysfunction. In general, benzodiazepines should be prescribed for short periods only due to the potential for dependence and cognitive impairment, and the availability of safer alternatives. 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. If possible, avoid coadministration of benzodiazepines and opioids due to the potential for profound sedation, respiratory depression, coma, and death; patients receiving the combination should be monitored for respiratory depression and sedation.

For the treatment of status epilepticus*:
NOTE: 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.
Intravenous 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/dose IV or IM as a single dose; may repeat dose once in 10 to 15 minutes.
Infants, Children, and Adolescents: 0.05 to 0.1 mg/kg/dose (Max: 4 mg/dose) IV or IM as a single dose; may repeat dose once in 5 to 15 minutes.

For the short-term management of anxiety:
Oral dosage:
Children* 1 to 11 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 older pediatric patients, the daily dosage for anxiety disorders is typically divided into 2 to 3 doses with a maximum of 10 mg/day.
Children and Adolescents 12 to 17 years: 2 to 3 mg/day PO in 2 to 3 divided doses, initially. May increase the dose gradually as needed. Usual dose: 2 to 6 mg/day. Max: 10 mg/day. When a higher dosage is needed, increase the evening dose before the daytime doses. Efficacy of long-term use (more than 4 months) for anxiety disorders has not been evaluated. To discontinue, taper the dose gradually.

For procedural sedation* and amnesia induction* and to control preoperative anxiety:
Oral dosage:
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:
Oral dosage:
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.
Intravenous dosage:
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:
Oral dosage:
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*:
Oral dosage:
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.
Intramuscular dosage:
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.
Intravenous dosage:
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:
-Neonates
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.
-Infants
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.
-Children
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.
-Adolescents
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.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Benzodiazepines act at the level of the limbic, thalamic, and hypothalamic regions of the CNS, and can produce any level of CNS depression required including sedation, hypnosis, skeletal muscle relaxation, anticonvulsant activity, and coma. The action of these drugs is mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Central benzodiazepine receptors interact allosterically with GABA receptors, potentiating the effects of GABA and thereby increasing the inhibition of the ascending reticular activating system. Benzodiazepine activity shows the highest affinity for GABA subtype A receptor modulation compared to subtype B receptors. Benzodiazepines block the cortical and limbic arousal that occurs following stimulation of the reticular pathways. Studies in healthy volunteers show that in single high doses, lorazepam has a tranquilizing action on the central nervous system with usually no appreciable effect on the respiratory or cardiovascular systems. Benzodiazepines can 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% 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 via UDP-glucuronosyltransferase (UGT) to lorazepam glucuronide, an inactive metabolite. In healthy adults, the elimination half-life when using immediate-release products 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 and drug transporters: UDP-glucuronosyltransferase (UGT)
Lorazepam is a substrate of UDP-glucuronosyltransferase (UGT). Concurrent administration of lorazepam with a UGT inhibitor may result in increased plasma concentrations, reduced clearance, and prolonged half-life of lorazepam.


-Route-Specific Pharmacokinetics
Oral Route
Lorazepam is readily absorbed following an oral dose, with a bioavailability of 90%. Subjective central nervous system effects occur within 1 to 2 hours. Peak plasma concentrations occur 2 hours following administration.

Intravenous Route
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.

Intramuscular Route
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.


-Special Populations
Pediatrics
Neonates
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.

Hepatic Impairment
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
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.

Hemodialysis
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.