Ativan ® (lorazepam)

Ativan ® (lorazepam)

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Ativan ® (lorazepam)

Ativan (lorazepam), an antianxiety agent, has the chemical formula, 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one: C15H10Cl2N2O2 M.W. 321.16

It is a nearly white powder almost insoluble in water. Each Ativan (lorazepam) tablet, to be taken orally, contains 0.5 mg, 1 mg, or 2 mg of lorazepam. The inactive ingredients present are lactose monohydrate, magnesium stearate, microcrystalline cellulose, and polacrilin potassium.

Indications and usage

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.

Clinical pharmacology

Studies in healthy volunteers show that in single high doses Ativan (lorazepam) has a tranquilizing action on the central nervous system with no appreciable effect on the respiratory or cardiovascular systems.

Ativan (lorazepam) is readily absorbed with an absolute bioavailability of 90%. Peak concentrations in plasma occur approximately 2 hours following administration. The peak plasma level of lorazepam from a 2 mg dose is approximately 20 ng/mL.

The mean half-life of unconjugated lorazepam in human plasma is about 12 hours and for its major metabolite, lorazepam glucuronide, about 18 hours. At clinically relevant concentrations, lorazepam is approximately 85% bound to plasma proteins. Ativan (lorazepam) is rapidly conjugated at its 3-hydroxy group into lorazepam glucuronide which is then excreted in the urine. Lorazepam glucuronide has no demonstrable central nervous system (CNS) activity in animals.

The plasma levels of lorazepam are proportional to the dose given. There is no evidence of accumulation of lorazepam on administration up to 6 months.

Studies comparing young and elderly subjects have shown that advancing age does not have a significant effect on the pharmacokinetics of lorazepam. However, in one study involving single intravenous doses of 1.5 to 3 mg of Ativan Injection, mean total body clearance of lorazepam decreased by 20% in 15 elderly subjects of 60 to 84 years of age compared to that in 15 younger subjects of 19 to 38 years of age.

Dosage and administration

Ativan (lorazepam) is administered orally. For optimal results, dose, frequency of administration, and duration of therapy should be individualized according to patient response. To facilitate this, 0.5 mg, 1 mg, and 2 mg tablets are available.

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.

Discontinuation or Dosage Reduction of Ativan

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Ativan or reduce the dosage. 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

Contraindications

Ativan (lorazepam) is contraindicated in patients with:

  • hypersensitivity to benzodiazepines or to any components of the formulation
  • acute narrow-angle glaucoma.

Warnings

Risks from Concomitant Use with Opioids: 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 in patients for whom alternative treatment options are inadequate.

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.

Abuse, Misuse, and Addiction: The use of benzodiazepines, including Ativan, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and 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, or death.

Dependence and Withdrawal Reactions: To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Ativan or reduce the dosage (a patient-specific plan should be used to taper the dose).

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer duration of use.

Acute Withdrawal Reactions: The continued use of benzodiazepines, including Ativan, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of Ativan after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening.

Protracted Withdrawal Syndrome: In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months.

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.

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.

Precautions

  • 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.
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  • 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. Dosage for patients with severe hepatic insufficiency should be adjusted carefully according to patient response; lower doses may be sufficient in such patients.
  • 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.

Drug interactions

Drug Interactions 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 exists. 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.

Use in specific populations

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. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant, they should communicate with their physician about the desirability of discontinuing the drug.

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.

Sedation and inability to suckle have occurred in neonates of lactating mothers taking benzodiazepines. Infants of lactating mothers should be observed for pharmacological effects (including sedation and irritability).

Geriatric Use: Clinical studies of Ativan generally were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects; however, the incidence of sedation and unsteadiness was observed to increase with age. Age does not appear to have a significant effect on lorazepam kinetics

Adverse reactions

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.

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).

Overdosage

In postmarketing 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.

Overdosage of benzodiazepines is usually manifested by varying degrees of CNS 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.

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.

Storage

Keep bottles tightly closed.

Keep out of reach of children.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Dispense in a tight container.

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