LORAZEPAM 2mg. Tablets.

BOXED WARNING

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 obstructive pulmonary disease (COPD), 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. Avoid use of lorazepam in patients with active alcoholism. 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.

DEA CLASS

Rx, schedule IV

DESCRIPTION

Oral and parenteral benzodiazepine; glucuronidated to inactive metabolites; used for anxiety disorders, acute ethanol withdrawal, preoperative sedation and amnesia; replaced diazepam as the preferred parenteral drug for status epilepticus due to longer persistence in the CNS.

COMMON BRAND NAMES

Ativan

HOW SUPPLIED

Ativan/Lorazepam Intramuscular Inj Sol: 1mL, 2mg, 4mg
Ativan/Lorazepam Intravenous Inj Sol: 1mL, 2mg, 4mg
Ativan/Lorazepam Oral Tab: 0.5mg, 1mg, 2mg
Lorazepam Oral Sol: 1mL, 2mg

DOSAGE & INDICATIONS

†Indicates off-label use

MAXIMUM DOSAGE

10 mg/day PO; maximum IM and IV dose highly variable dependent upon indication.

10 mg/day PO; maximum IM and IV dose highly variable depending upon indication.

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.

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
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.

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.

DOSING CONSIDERATIONS

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.

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.

ADMINISTRATION

Tablets and oral solution concentrate are available to be administered orally. In some countries, a sublingual† dosage form is available; some published literature describes the effective sublingual administration† of available oral tablets, particularly in pre-operative use; chronic use of this administration route is not well-supported.

For intravenous or intramuscular administration only. Do not administer lorazepam injection by intra-arterial injection since arteriospasm can occur which may cause tissue damage and/or gangrene.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

STORAGE

Generic:
– Discard opened bottle after 90 days
– Protect from light
– Store between 36 to 46 degrees F
Ativan:
– Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

CONTRAINDICATIONS / PRECAUTIONS

Lorazepam is contraindicated in any patient with a known lorazepam or benzodiazepine hypersensitivity. Lorazepam injection is contraindicated in patients who are hypersensitive to other ingredients in these products (i.e., propylene glycol or polyethylene glycol). Too much propylene glycol can cause central nervous system toxicity such as seizures and intraventricular hemorrhage, unresponsiveness, tachypnea, tachycardia, and diaphoresis. Some formulations of lorazepam injection also contain benzyl alcohol and are contraindicated in patients with known benzyl alcohol hypersensitivity. Of note, normal therapeutic lorazepam injectable doses contain very small amounts of propylene glycol, polyethylene glycol, and benzyl alcohol.

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.

The use of injectable benzodiazepines, like lorazepam, in status epilepticus 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.

Injectable lorazepam is contraindicated for intraarterial administration due to the possibility of arteriospasm and resultant gangrene that may require amputation.

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 obstructive pulmonary disease (COPD), 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. Avoid use of lorazepam in patients with active alcoholism. 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 ambulate. No patient should get out of bed unassisted within 8 hours of lorazepam injection. In addition, patients should not attempt driving or operating machinery 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.

Injectable and oral lorazepam formulations are contraindicated in patients with acute closed-angle glaucoma. The mechanistic rational for this contraindication has been questioned, as benzodiazepines do not have antimuscarinic activity and do not raise intraocular pressure. Benzodiazepines may be used in patients with open-angle glaucoma who are receiving appropriate therapy.

Benzodiazepines should be administered cautiously to patients with renal impairment or renal failure, hepatic disease or hepatic encephalopathy; liver and renal function should be monitored regularly during prolonged therapy. As with all benzodiazepines, the use of lorazepam may worsen hepatic encephalopathy and should be used cautiously in severe hepatic impairment. Because lorazepam undergoes conjugative metabolism as opposed to oxidative metabolism, it is relatively safer to use in patients with hepatic dysfunction with careful clinical monitoring versus other benzodiazepines.

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. Generally, benzodiazepines should be prescribed for short periods (2 to 4 weeks) with continued reevaluation of the need for treatment. Tolerance (or tachyphylaxis) may develop to the sedative effects of benzodiazepines. Patients should be questioned about the need for escalating doses, and the clinician may need to intervene to prevent further tolerance or increased risk for addiction. Abrupt discontinuation of lorazepam after prolonged use should be avoided. Abrupt discontinuation of benzodiazepine therapy has been reported to cause withdrawal symptoms, especially following high dose or prolonged therapy. However, benzodiazepine dependence can occur following administration of therapeutic doses for as few as 1 to 2 weeks, and withdrawal symptoms may be seen following the discontinuation of therapy. Benzodiazepine withdrawal can be more intense with short-acting benzodiazepines such as lorazepam. Patients with a history of a seizure disorder or who are taking other drugs that lower the seizure threshold (i.e., tricyclic antidepressants, phenothiazines) should not be withdrawn abruptly from benzodiazepines due to the risk of precipitating a seizure. Benzodiazepines should be withdrawn slowly, using a gradual dosage-tapering schedule. During withdrawal, the greatest risk of seizure appears to be during the first 24 to 72 hours.

Lorazepam should be used with caution in patients with a neuromuscular disease, such as muscular dystrophy, myotonia, or myasthenia gravis as these conditions can be exacerbated. Patients with late stage Parkinson’s disease may experience worsening of their psychosis or impaired cognition with administration of benzodiazepines. Benzodiazepines may also cause incoordination or paradoxical reactions that may worsen symptoms of Parkinson’s disease.

Lorazepam has not been shown to be effective for comorbid conditions associated with anxiety (i.e., cardiovascular or gastrointestinal disorders). Esophageal dilation has been shown to occur in rats with high doses (6 mg/kg/day) and prolonged therapy (more than 1 year) of lorazepam. The effect was reversible only if therapy was stopped within 2 months of observation. Although the clinical significance is not known, patients utilizing lorazepam for prolonged periods should have frequent evaluation for symptoms of upper GI disease.

Clinical studies of lorazepam generally were not adequate to determine whether geriatric subjects respond differently than younger adults, however, adult patients over 50 years of age may experience a greater incidence of central nervous system (CNS) depression and more respiratory depression, particularly with preanesthetic use. Age does not appear to have a clinically significant effect on lorazepam kinetics alone. Clinical circumstances, some of which may be more common in the geriatric adult, such as hepatic or renal impairment, should be considered. In general, dose selection for the geriatric patient should be cautious, usually starting at the low end of the dosing range. According to the Beers Criteria, benzodiazepines are considered potentially inappropriate medications (PIMs) for use in geriatric patients and avoidance is generally recommended, although some agents from this class may be appropriate for seizure disorders, rapid eye movement sleep disorders, benzodiazepine withdrawal, severe generalized anxiety disorder, peri-procedural anesthesia, and end of life care. Older adults have an increased sensitivity to benzodiazepines. In general, all benzodiazepines increase the risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents in older adults. The Panel recommends avoiding benzodiazepines in geriatric patients with the following disease states or symptoms due to the potential for exacerbation of the condition or increased risk of adverse effects: delirium (possible new-onset or worsening delirium), dementia (adverse CNS effects), and history of falls/fractures (ataxia, impaired psychomotor function, syncope, and additional falls). If a benzodiazepine must be used in a patient with a history of falls or fractures, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk.  The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). Specific criteria for anxiolytics must be met, including 1) limiting use to indications specified in the OBRA guidelines (e.g., generalized anxiety disorder, panic disorder, significant anxiety to a situational trigger, alcohol withdrawal) which meet the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for the indication, and 2) evidence exists that other possible reasons for the individual’s distress have been considered, and 3) use results in maintenance or improvement in mental, physical, and psychosocial well-being as reflected on the Minimum Data Set (MDS) or other assessment tool. Anxiolytics should be used for delirium, dementia, or other cognitive disorders only when there are associated behaviors that are 1) quantitatively and objectively documented, and 2) are persistent, and 3) are not due to preventable or correctable reasons, and 4) constitute clinically significant distress or dysfunction to the LTCF resident or represent a danger to the resident or others. There are exceptions that may warrant the use of an anxiolytic such as a long-acting benzodiazepine for withdrawal from a short-acting benzodiazepine, use for neuromuscular syndromes (e.g., tardive dyskinesia, restless legs syndrome, seizure disorder, cerebral palsy), or end of life care. The need for indefinite continuation of lorazepam (e.g., seizure disorder) should be based on confirmation of the condition being treated and its potential cause(s). When lorazepam is used as a sedative, factors potentially causing insomnia should be evaluated before medication initiation (e.g., sleep environment, inadequate physical activity, provision of care disruptions, caffeine or medications, pain and discomfort, or other underlying conditions that cause insomnia). Initiation of sleep induction or maintenance medication should be preceded or accompanied by non-pharmacologic interventions and maximized treatment of underlying conditions (if applicable). All sleep medications should be used in accordance with approved product labeling. The use of sedating medications for individuals with diagnosed sleep apnea requires careful assessment, documented clinical rationale, and close monitoring. Exceptions to the OBRA provisions include: single dose sedative use for a dental or medical procedure or short-term sedative use during initiation of treatment for depression, pain, or other comorbid condition until symptoms improve or the underlying causative factor can be identified and/or effectively treated. It should be noted that benzodiazepines may increase the risk of confusion, sedation, and falls. OBRA provides dosing guidance for lorazepam as an anxiolytic and a sedative. When a medication is used to induce sleep, treat a sleep disorder, manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.

Benzodiazepines may cause harm to the fetus when administered to pregnant women. An increased risk of congenital malformations during the first trimester of pregnancy has been suggested in several studies involving minor tranquilizers, including benzodiazepines. When benzodiazepines are administered late in pregnancy, they are easily transferred to the fetus where they have the potential to accumulate, causing 2 major neonatal syndromes: a neonatal abstinence syndrome (NAS) and floppy infant syndrome (FIS). Symptoms of NAS from case reports include tremors, irritability, hyperactivity, hypertonicity, tachypnea, vigorous sucking, poor weight gain, loose stools, and vomiting. FIS symptoms include hypotonia, inactivity, weak cry, lethargy, sucking difficulties, low Apgar score, hypothermia, apnea, cyanosis, hyperbilirubinemia, and central nervous system (CNS) depression. FIS typically occurs after chronic fetal exposure to long-acting benzodiazepines (e.g., chlordiazepoxide), 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. Therefore, benzodiazepines are not recommended for use in obstetrical procedures, labor, or obstetric delivery, including cesarean section. 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). It should be noted that in some case series and studies conducted on specific benzodiazepines, including lorazepam, there was no evidence of neonatal toxicity or withdrawal syndromes in newborns exposed in utero. Nevertheless, if a benzodiazepine is required during pregnancy, avoid first trimester administration if possible, consider short-acting agents (e.g., lorazepam, oxazepam), limit treatment to the shortest possible duration and lowest effective dose, and discontinue the drug well before delivery. According to FDA-approved labeling for lorazepam injection, the drug should not be given to a pregnant woman except in serious or life-threatening situations (e.g., status epilepticus) where safer drugs cannot be used or are ineffective. The possibility that a woman of childbearing potential may be pregnant at the time of treatment initiation should be considered. Patients who become pregnant or intend to become pregnant while taking lorazepam should be advised to discuss the possibility of discontinuing the drug with their physician. Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures during the third trimester of pregnancy may have negative effects on fetal brain development. Consider the benefits of appropriate anesthesia in pregnant women against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required prior to delivery. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child and/or mother. 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.

Lorazepam should generally not be administered to breast-feeding mothers. Lorazepam is excreted into human breast milk in low levels. In a study of 4 lactating women, concentrations of free lorazepam in breast milk 4 hours after a single 3.5 mg oral dose were found to be 8 to 9 ng/mL, which accounted for 14.8% to 25.7% of the mother’s plasma concentration. In a separate case, a woman taking lorazepam 2.5 mg PO twice daily for the first 5 days postpartum had milk concentrations of free and conjugated lorazepam of 12 and 35 mcg/L, respectively, at an unspecified time on day 5, and her infant showed no signs of sedation. In a retrospective cohort study of breast-feeding mothers using a benzodiazepine (n = 124), sedation was not reported in any infant exposed to lorazepam through breast milk (52% of participants). According to a evidence-based analysis designed to provide information about breast-fed infant drug exposure concentrations and adverse events, the amount of sedative or hypnotic exposure in the breast-fed infant is not very high; however, caution is recommended since neonatal metabolism of benzodiazepines occurs more slowly than in adults, and when used chronically, accumulation may occur in the infant producing sedation, nausea, poor feeding, or other adverse effects, particularly with long-acting benzodiazepines (e.g., diazepam, chlordiazepoxide). If a benzodiazepine must be used, a short-acting agent such as oxazepam or lorazepam should be selected, and administered at the minimum dosage and duration required for symptom relief. The infant should be monitored regularly, and if sedation, nausea, reduced suckling, or other signs of toxicity are observed, either breast-feeding or the benzodiazepine should be discontinued.

Both oral and injectable lorazepam solutions contain propylene glycol and polyethylene glycol. Lorazepam injection also contains benzyl alcohol as a preservative. Pediatric patients, in particular premature neonates and term neonates, may be more sensitive to these compounds. Lorazepam injection is contraindicated in premature neonates due to its benzyl alcohol content. 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 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. Infants and children are also more susceptible to the therapeutic effects of benzodiazepines. Although commonly used off-label in the pediatric population, safe and effective use of oral and parenteral lorazepam has not been established in pediatric patients younger than 12 years and 18 years, respectively.