Medications: Ativan^® – lorazepam

Ativan (lorazepam) is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety or anxiety associated with depressive symptoms. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The effectiveness of Ativan (lorazepam) in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.

DOSAGE AND ADMINISTRATION

• The usual range is 2 to 6 mg/day given in divided doses, the largest dose being taken before bedtime, but the daily dosage may vary from 1 to 10 mg/day.
• For anxiety, most patients require an initial dose of 2 to 3 mg/day given two times a day or three times a day.
• For insomnia due to anxiety or transient situational stress, a single daily dose of 2 to 4 mg may be given, usually at bedtime.
• For elderly or debilitated patients, an initial dosage of 1 to 2 mg/day in divided doses is recommended, to be adjusted as needed and tolerated.

The dosage of Ativan (lorazepam) should be increased gradually when needed to help avoid adverse effects. When higher dosage is indicated, the evening dose should be increased before the daytime doses

Most adverse reactions to benzodiazepines, including CNS effects and respiratory depression, are dose dependent, with more severe effects occurring with high doses.

In a sample of about 3500 patients treated for anxiety, the most frequent adverse reaction to Ativan (lorazepam) was sedation (15.9%), followed by dizziness (6.9%), weakness (4.2%), and unsteadiness (3.4%). The incidence of sedation and unsteadiness increased with age.

Other adverse reactions to benzodiazepines, including lorazepam are fatigue, drowsiness, amnesia, memory impairment, confusion, disorientation, depression, unmasking of depression, disinhibition, euphoria, suicidal ideation/attempt, ataxia, asthenia, extrapyramidal symptoms, convulsions/seizures, tremor, vertigo, eye function/visual disturbance (including diplopia and blurred vision), dysarthria/slurred speech, change in libido, impotence, decreased orgasm; headache, coma; respiratory depression, apnea, worsening of sleep apnea, worsening of obstructive pulmonary disease; gastrointestinal symptoms including nausea, change in appetite, constipation, jaundice, increase in bilirubin, increase in liver transaminases, increase in alkaline phosphatase; hypersensitivity reactions, anaphylactoid reactions; dermatological symptoms, allergic skin reactions, alopecia; SIADH, hyponatremia; thrombocytopenia, agranulocytosis, pancytopenia; hypothermia; and autonomic manifestations.

Paradoxical reactions, including anxiety, excitation, agitation, hostility, aggression, rage, sleep disturbances/insomnia, sexual arousal, and hallucinations may occur.

Small decreases in blood pressure and hypotension may occur but are usually not clinically significant, probably being related to the relief of anxiety produced by Ativan (lorazepam).

Ativan (lorazepam) is contraindicated in patients with

– hypersensitivity to benzodiazepines or to any components of the formulation.

– acute narrow-angle glaucoma.

WARNINGS AND PRECAUTIONS:

• Concomitant use of benzodiazepines, including Ativan, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Advise both patients and caregivers about the risks of respiratory depression and sedation when Ativan is used with opioids.
• Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see PRECAUTIONS, Clinically Significant Drug Interactions).
• Pre-existing depression may emerge or worsen during use of benzodiazepines including lorazepam.
• Ativan (lorazepam) is not recommended for use in patients with a primary depressive disorder or psychosis.
• Use of benzodiazepines, including lorazepam, both used alone and in combination with other CNS depressants, may lead to potentially fatal respiratory depression. (See PRECAUTIONS, Clinically Significant Drug Interactions.)
• Use of benzodiazepines, including lorazepam, may lead to physical and psychological dependence.
• As with all patients on CNS-depressant drugs, patients receiving lorazepam should be warned not to operate dangerous machinery or motor vehicles and that their tolerance for alcohol and other CNS depressants will be diminished.
• In general, benzodiazepines should be prescribed for short periods only (e.g., 2 to 4 weeks). Extension of the treatment period should not take place without reevaluation of the need for continued therapy. Continuous long-term use of product is not recommended.
• Withdrawal symptoms (e.g., rebound insomnia) can appear following cessation of recommended doses after as little as one week of therapy. Abrupt discontinuation of product should be avoided, and a gradual dosage-tapering schedule followed after extended therapy. Abrupt termination of treatment may be accompanied by withdrawal symptoms.
• Lorazepam may have abuse potential, especially in patients with a history of drug and/or alcohol abuse.
• In patients with depression, a possibility for suicide should be borne in mind; benzodiazepines should not be used in such patients without adequate antidepressant therapy.
• Lorazepam should be used with caution in patients with compromised respiratory function (e.g., COPD, sleep apnea syndrome).
• Elderly or debilitated patients may be more susceptible to the sedative effects of lorazepam. Therefore, these patients should be monitored frequently and have their dosage adjusted carefully according to patient response; the initial dosage should not exceed 2 mg.
• Paradoxical reactions have been occasionally reported during benzodiazepine use. Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued.
• The usual precautions for treating patients with impaired renal or hepatic function should be observed.
• As with all benzodiazepines, the use of lorazepam may worsen hepatic encephalopathy; therefore, lorazepam should be used with caution in patients with severe hepatic insufficiency and/or encephalopathy.
• In patients where gastrointestinal or cardiovascular disorders coexist with anxiety, it should be noted that lorazepam has not been shown to be of significant benefit in treating the gastrointestinal or cardiovascular component.
• Safety and effectiveness of Ativan (lorazepam) in children of less than 12 years have not been established.
• Essential Laboratory Tests: Some patients on Ativan (lorazepam) have developed leukopenia, and some have had elevations of LDH. As with other benzodiazepines, periodic blood counts and liver function tests are recommended for patients on long-term therapy.
• Pregnancy: an increased risk of congenital malformations associated with the use of minor tranquilizers (chlordiazepoxide, diazepam, and meprobamate) during the first trimester of pregnancy has been suggested in several studies. Because the use of these drugs is rarely a matter of urgency, the use of lorazepam during this period should be avoided.
• Nursing mothers: Lorazepam has been detected in human breast milk; therefore, it should not be administered to breastfeeding women, unless the expected benefit to the woman outweighs the potential risk to the infant.
• Caution with geriatric use

The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation.

The benzodiazepines, including Ativan (lorazepam), produce increased CNS-depressant effects when administered with other CNS depressants such as alcohol, barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anesthetics.

Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, hypotension, ataxia, delirium, and respiratory arrest.

Concurrent administration of lorazepam with valproate results in increased plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage should be reduced to approximately 50% when coadministered with valproate.

Concurrent administration of lorazepam with probenecid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid.

The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation.

Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam.

m with probenecid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid.

The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation.

Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam.

In post marketing experience, overdose with lorazepam has occurred predominantly in combination with alcohol and/or other drugs. Therefore, in the management of overdosage, it should be borne in mind that multiple agents may have been taken.

Symptoms: Overdosage of benzodiazepines is usually manifested by varying degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion, paradoxical reactions, dysarthria and lethargy. In more serious cases, and especially when other drugs or alcohol were ingested, symptoms may include ataxia, hypotonia, hypotension, cardiovascular depression, respiratory depression, hypnotic state, coma, and death.

Management: General supportive and symptomatic measures are recommended; vital signs must be monitored, and the patient closely observed. When there is a risk of aspiration, induction of emesis is not recommended. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Administration of activated charcoal may also limit drug absorption. Hypotension, though unlikely, usually may be controlled with norepinephrine bitartrate injection. Lorazepam is poorly dialyzable. Lorazepam glucuronide, the inactive metabolite, may be highly dialyzable. The benzodiazepine antagonist flumazenil may be used in hospitalized patients as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package-insert including Contraindications, Warnings, and Precautions should be consulted prior to use.