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ATIVAN (lorazepam)
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ATIVAN Quick Finder
1 Indications
ATIVAN is indicated for:
- the short-term relief of manifestations of excessive anxiety in patients with anxiety neurosis.
- An adjunct for the relief of excessive anxiety that might be present prior to surgical interventions.
Anxiety and tension associated with the stresses of everyday life usually do not require treatment with anxiolytic drugs.
1.1 Pediatrics
Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
1.2 Geriatrics
Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness.
Long-term use of ATIVAN should be avoided in geriatric patients. Enhanced monitoring is recommended (see 7 WARNINGS AND PRECAUTIONS, Falls and fractures; 4 DOSAGE AND ADMINISTRATION, 4.2 Dosing considerations).
2 Contraindications
- ATIVAN is contraindicated in patients with myasthenia gravis or acute narrow angle glaucoma and in those with known hypersensitivity to benzodiazepines.
- ATIVAN is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
3 Serious Warnings And Precautions Box
Serious Warnings and Precautions
Addiction, Abuse and Misuse
The use of benzodiazepines, including ATIVAN can lead to abuse, misuse, addiction, physical dependence and withdrawal reactions. Abuse and misuse can result in overdose or death, especially when benzodiazepines are combined with other medicines, such as opioids, alcohol or illicit drugs.
- Assess each patient’s risk prior to prescribing ATIVAN
- Monitor all patients regularly for the development of these behaviours or conditions
- ATIVAN should be stored securely to avoid theft or misuse
Withdrawal
Benzodiazepines, like ATIVAN can produce severe or life-threatening withdrawal symptoms
- Avoid abrupt discontinuation or rapid dose reduction of ATIVAN
- Terminate treatment with ATIVAN by gradually tapering the dosage schedule under close monitoring
(see 7 WARNINGS AND PRECAUTIONS, Dependence/Tolerance)
Risks from Concomitant use with Opioids
Concomitant use of ATIVAN and opioids may result in profound sedation, respiratory depression, coma and death (see 7 WARNINGS AND PRECAUTIONS – Risks from concomitant use of opioids and benzodiazapines).
- Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate
- Limit dosages and durations to the minimum required
- Follow patients for signs and symptoms of respiratory depression and sedation
4 Dosage And Administration
4.1 Dosing Considerations
- ATIVAN should always be prescribed at the lowest effective dose for the shortest duration possible.
- ATIVAN can produce withdrawal signs and symptoms or rebound phenomena following abrupt discontinuation or rapid dose reduction (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Withdrawal; 7 WARNINGS AND PRECAUTIONS, Dependence/Tolerance). Abrupt discontinuation should be avoided and treatment - even if only of short duration - should be terminated by gradually tapering the dosage schedule under close monitoring. Withdrawal symptoms (e.g., rebound insomnia) can appear following cessation of recommended doses after as little as one week of therapy.
- Tapering should be tailored to the specific patient. Special attention should be given to patients with a history of seizure.
- If a patient experiences withdrawal signs and symptoms, consider postponing the taper or raising the benzodiazepine to the previous dosage prior to proceeding with a gradual taper.
Symptoms reported following discontinuation of benzodiazepines include: headache, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, rebound phenomena, dysphoria, dizziness, derealization, depersonalization, hyperacusis, numbness/tingling of extremities, hypersensitivity to light, noise and physical contact/perceptual changes, involuntary movements, nausea, vomiting, diarrhea, loss of appetite, hallucinations,/delirium, convulsions/seizures, tremor, abdominal and muscle cramps, myalgia, agitation, palpitations, tachycardia, panic attacks, vertigo, hyperreflexia, short-term memory loss, and hyperthermia. Convulsions/seizures may be more common in patients with pre-existing seizure disorders or who are taking other drugs that lower the convulsive threshold, such as antidepressants.
Renal or hepatic disease
The dose should be titrated should ATIVAN be used in patients with mild to moderate hepatic or renal disease. In patients for whom prolonged therapy with ATIVAN is indicated, periodic blood counts and liver function tests should be carried out.
When lorazepam is used in patients with mild to moderate hepatic or renal disease, the lowest effective dose should be considered since drug effect may be prolonged.
(see 7 WARNINGS AND PRECAUTIONS, Renal)
Geriatrics
For geriatric patients and debilitated patients reduce the initial dose by approximately 50% and adjust the dosage as needed and tolerated. Geriatric patients in particular may be more sensitive to benzodiazepines (see 7 WARNINGS AND PRECAUTIONS, Falls and Fractures). Long-term use of ATIVAN should be avoided in geriatric patients. Enhanced monitoring is recommended.(See 7.1.4 Geriatrics)
4.2 Recommended Dose and Dosage Adjustment
The dosage and duration of therapy of ATIVAN (lorazepam) must be individualized and carefully titrated in order to avoid excessive sedation or mental and motor impairment.
As with other anxiolytic sedatives, short courses of treatment should usually be the rule for the symptomatic relief of disabling anxiety in psychoneurotic patients and the initial course of treatment should not last longer than one week without reassessment of the need for a limited extension. Initially, not more than one week's supply of the drug should be provided, and automatic prescription renewals should not be allowed. Subsequent prescriptions, when required, should be limited to short courses of therapy.
The risk of dependence may increase with dose and duration of treatment; therefore, the lowest effective dose should be prescribed for the shortest duration and the need for continued treatment reassessed frequently.
Abrupt discontinuation or rapid dosage reduction of lorazepam after continued use may precipitate withdrawal reactions which can be life threatening, and/or rebound phenomena; therefore, the drug should be discontinued gradually or reduce the dosage (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Withdrawal; 7 WARNINGS AND PRECAUTIONS, Dependence/Tolerance).
Generalized Anxiety Disorder: The recommended initial adult daily oral dosage is 2 mg in divided doses of 0.5, 0.5 and 1mg, or of 1 mg and 1 mg. The daily dosage should be carefully increased or decreased by 0.5 mg depending upon tolerance and response. The usual daily dosage is 2 to 3mg. However, the optimal dosage may range from 1 to 4 mg daily in individual patients. Usually, a daily dosage of 6 mg should not be exceeded.
In geriatric and debilitated patients, the initial daily dose should not exceed 0.5 mg and should be very carefully and gradually adjusted, depending upon tolerance and response.
Excessive Anxiety Prior to Surgical Procedures: Adults: Usually 0.05 mg/kg to a maximum of 4 mg total, given by the sublingual route 1 to 2 hours before surgery. As with all premedicant drugs, the dose should be individualized. Doses of other central nervous system depressant drugs should be ordinarily reduced.
Health Canada has not authorized an indication for pediatric use.
4.4 Administration
The sublingual tablet, when placed under the tongue, will dissolve in approximately 20 seconds. The patients should not swallow for at least 2 minutes to allow sufficient time for absorption.
4.5 Missed Dose
Patients who miss taking a dose should contact their healthcare provider for instructions.
5 Overdosage
In post-marketing experience, overdose with lorazepam has occurred predominantly in combination with alcohol and/or other drugs.
Symptoms: With benzodiazepines, including lorazepam, symptoms of mild overdosage include drowsiness, mental confusion and lethargy. In more serious overdoses, symptoms may include ataxia, hypotonia, hypotension, hypnosis, Stages I to III coma, and, very rarely, death. Symptoms can range in severity and include, in addition to the above, dysarthria, paradoxical reactions, CNS depression, respiratory depression, and cardiovascular depression.
Treatment: In the case of an oral overdose, if vomiting has not occurred spontaneously and the patient is fully awake, emesis may be induced with syrup of ipecac 20-30 mL (where there is risk of aspiration, induction of emesis is not recommended). Gastric lavage should be instituted as soon as possible and 50-100 g of activated charcoal should be introduced to and left in the stomach.
Lorazepam is poorly dialyzable. Lorazepam glucuronide, the inactive metabolite, may be highly dialyzable.
General supportive therapy should be instituted as indicated. Vital signs and fluid balance should be carefully monitored. An adequate airway should be maintained and assisted respiration used as needed. With normally functioning kidneys, forced diuresis with intravenous fluids and electrolytes may accelerate elimination of benzodiazepines from the body. In addition, osmotic diuretics such as mannitol may be effective as adjunctive measures. In more critical situations, renal dialysis and exchange blood transfusions may be indicated. Published reports indicate that intravenous infusion of 0.5 to 4 mg of physostigmine at the rate of 1 mg/minute may reverse symptoms and signs suggestive of central anticholinergic overdose (confusion, memory disturbance, visual disturbances, hallucinations, delirium); however, hazards associated with the use of physostigmine (i.e., induction of seizures) should be weighed against its possible clinical benefit.
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 physician should be aware of the risk of a seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose.
For management of a suspected drug overdose, contact your regional poison control centre.
6 Dosage Forms, Strengths, Composition And Packaging
| Route of Administration | Dosage Form / Strength/Composition | Non-medicinal Ingredients |
|---|---|---|
| Oral | Tablet, 0.5 mg, 1 mg, 2 mg | Lactose, magnesium stearate, microcrystalline cellulose, polacrilin potassium |
| Sublingual | Tablet, 0.5 mg. 1 mg, 2 mg | Each 0.5 mg. 1 mg, 2 mg contains: Corn starch, lactose, magnesium stearate, microcrystalline cellulose In addition, each 0.5 mg contains: D&C yellow 10 aluminum lake, FD&C blue 1 aluminum lake, FD&C yellow 6 aluminum lake In addition, each 2 mg: FD&C blue 2 aluminum lake |
ATIVAN oral and sublingual tablets are available in high density polyethylene bottles.
Oral Tablets: 0.5 mg bottles of 500, 1 mg and 2 mg in bottles of 1000
Sublingual Tablets: 0.5 mg, 1 mg and 2 mg in bottles of 100
7 Warnings And Precautions
Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX
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 for use in patients for whom alternative treatment options are not possible (see SERIOUS WARNINGS AND PRECAUTIONS BOX, Risks from Concomitant Use with Opioids; DRUG INTERACTIONS, Serious Drug Interactions).
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with benzodiazepines.
If a decision is made to prescribe ATIVAN concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of ATIVAN than indicated, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking ATIVAN, prescribe a lower initial dose of the opioid analgesic and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation (see OVERDOSAGE).
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 of the opioid have been determined.
Dependence/Tolerance
Use of benzodiazepines such as ATIVAN can lead to abuse, misuse, addiction, physical dependence (including tolerance) and withdrawal reactions. Abuse and misuse can result in overdose or death, especially when benzodiazepines are combined with other medicines, such as opioids, alcohol or illicit drugs. Benzodiazepines may be subject to diversion.
The risk of dependence increases with higher doses and longer term use but can occur with short-term use at recommended therapeutic doses. The risk of dependence is greater in patients with a history of psychiatric disorders and/or substance (including alcohol) use disorder. Interdose daytime anxiety and rebound anxiety may increase the risk of dependency in ATIVAN treated patients.
- Discuss the risks of treatment with ATIVAN with the patient, considering alternative (including non-drug) treatment options.
- Carefully evaluate each patient’s risk of abuse, misuse and addiction, considering their medical condition and concomitant drug use, prior to prescribing ATIVAN. In individuals prone to substance use disorder, ATIVAN should only be administered if deemed medically necessary, employing extreme caution and close supervision.
- ATIVAN should always be prescribed at the lowest effective dose for the shortest duration possible.
- All patients receiving benzodiazepines should be monitored for signs of misuse and abuse. If a substance use disorder is suspected, evaluate the patient and refer them for substance abuse treatment, as appropriate.
Withdrawal: Benzodiazepines, such as ATIVAN, can produce withdrawal signs and symptoms, ranging from mild to severe and even life threatening, following abrupt discontinuation or rapid dose reduction. Other factors that may precipitate withdrawal are switching from a long-acting to a short-acting benzodiazepine, decreasing blood levels of the drug or administration of an antagonist. The risk of withdrawal is higher with higher dosages and/or prolonged use, but can occur with short-term use (days to weeks) at recommended therapeutic doses.
The onset of withdrawal signs and symptoms can range from hours to weeks following drug cessation and occur even with tapered dosage. Some symptoms can persist for months. Since symptoms are often similar to those for which the patient is being treated, it may difficult to distinguish from a relapse of the patient’s condition.
Severe or life-threatening signs and symptoms of withdrawal include catatonia delirium tremens, depression, dissociative effects (e.g. hallucinations), mania, psychosis, seizures (including status epilepticus) and suicidal ideation and behavior have been observed.
Other withdrawal signs and symptoms include abdominal and muscle cramps, cognitive impairment, diarrhea, dysphoria, extreme anxiety or panic attacks, headache, hypersensitivity to light, noise and physical contact, insomnia, irritability, muscle pain or stiffness, paresthesia, restlessness, sweating, tension, tremors and vomiting. There is also a possibility of rebound anxiety or rebound insomnia.
- Abrupt discontinuation should be avoided and treatment - even if only of short duration - should be terminated by gradually tapering the dosage schedule under close monitoring.
- Tapering should be tailored to the specific patient. Special attention should be given to patients with a history of seizure.
- If a patient experiences withdrawal signs and symptoms, consider postponing the taper or raising the benzodiazepine to the previous dosage prior to proceeding with a gradual taper.
- Inform patients of risk of discontinuing abruptly, reducing dosage rapidly or switching medications.
- Stress the importance of consulting with their health care professional in order to discontinue safely.
- Patients experiencing withdrawal signs and symptoms should seek immediate medical attention.
(see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Addiction, Abuse and Misuse, Withdrawal; 4 DOSAGE AND ADMINISTRATION, 4.1 Dosing Considerations)
Driving and Operating Machinery
Excessive sedation has been observed with lorazepam at standard therapeutic doses. Therefore, patients on ATIVAN should be warned against engaging in hazardous activities requiring mental alertness and motor coordination, such as operating dangerous machinery or driving motor vehicles.
As is true of other similar CNS-acting drugs, patients receiving lorazepam should not operate machinery or engage in hazardous occupations or drive a motor vehicle for a period of 24 to 48 hours. Impairment of performance may persist for greater intervals because of extremes of age, concomitant use of other drugs, stress of surgery or the general condition of the patient.
Falls and Fractures
There have been reports of falls and fractures among benzodiazepine users due to adverse reactions such as sedation, dizziness and ataxia. The risk is increased in those taking concomitant sedatives (including alcoholic beverages), geriatric or debilitated patients.
Immune
Severe anaphylactic/anaphylactoid reactions have been reported with the use of benzodiazepines. Cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of benzodiazepines. Some patients taking benzodiazepines have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with a benzodiazepine should not be rechallenged with the drug.
Neurologic
Since ATIVAN has a central nervous system depressant effect, patients should be advised against the simultaneous use of other CNS depressant drugs.
Psychiatric
ATIVAN is not recommended for use in depressive neurosis or in psychotic reactions.
Use in Mental and Emotional Disorders: ATIVAN is not recommended for the treatment of psychotic or depressed patients. Since excitement and other paradoxical reactions can result from the use of these drugs in psychotic patients, they should not be used in ambulatory patients suspected of having psychotic tendencies.
As with other anxiolytic-sedative drugs, lorazepam should not be used in patients with non-pathological anxiety. These drugs are also not effective in patients with characterological and personality disorders or those with obsessive-compulsive neurosis.
When using ATIVAN, it should be recognized that suicidal tendencies may be present and that protective measures may be required.
Pre-existing depression may emerge or worsen during use of benzodiazepines including lorazepam. The use of benzodiazepines may unmask suicidal tendencies in depressed patients and should not be used without adequate antidepressant therapy.
Renal
Use in Patients with Impaired Renal or Hepatic Function: Since the liver is the most likely site of conjugation of lorazepam and since excretion of conjugated lorazepam (glucuronide) is a renal function, the usual precaution of carefully titrating the dose should be taken, should ATIVAN be used in patients with mild to moderate hepatic or renal disease. In patients for whom prolonged therapy with ATIVAN is indicated, periodic blood counts and liver function tests should be carried out.
When lorazepam is used in patients with mild to moderate hepatic or renal disease, the lowest effective dose should be considered since drug effect may be prolonged.
Dosage for patients with severe hepatic insufficiency should be adjusted carefully according to patient response. Lower doses may be sufficient in such patients.
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.
Reproductive Health: Female and Male Potential
- Teratogenic Risk
Use in Pregnancy: ATIVAN should not be used during pregnancy. Several studies have suggested an increased risk of congenital malformations associated with the use of the benzodiazepines during pregnancy (see 16 NON-CLINICAL TOXICOLOGY).
Infants of mothers who ingested benzodiazepines for several weeks or more preceding delivery have been reported to have withdrawal symptoms during the postnatal period. Symptoms such as hypoactivity, hypotonia, hypothermia, respiratory depression, apnea, feeding problems, and impaired metabolic response to cold stress have been reported in neonates born of mothers who have received benzodiazepines during the late phase of pregnancy or at delivery.
Since lorazepam is also a benzodiazepine derivative, its administration is rarely justified in women of child-bearing potential. If the drug is prescribed to a woman of child-bearing potential, she should be warned to contact her physician regarding discontinuation of the drug if she intends to become or suspects that she is pregnant.
In women, blood levels obtained from umbilical cord blood indicate placental transfer of lorazepam and lorazepam glucuronide. ATIVAN Injection should not be used during pregnancy. There are insufficient data regarding obstetrical safety of parenteral lorazepam, including use in caesarean section. Such use, therefore, is not recommended.
Respiratory
ATIVAN should be used with caution in patients with compromised respiratory function (e.g., COPD, sleep apnea syndrome).
7.1 Special Populations
7.1.1 Pregnant Women
ATIVAN should not be used during pregnancy.
7.1.2 Breastfeeding
Use in 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 mother 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).
7.1.3 Pediatrics
Use in Children: ATIVAN is not intended for use in children under 18 years of age. The safety and effectiveness of ATIVAN in children less than 18 years of age has not been established (see 16 NONCLINICAL TOXICOLOGY). Because of the lack of sufficient clinical experience, ATIVAN is not recommended for use in patients less than 18 years of age (see 7 WARNINGS AND PRECAUTIONS).
Paradoxical reactions have been occasionally reported during benzodiazepine use (See 8 ADVERSE REACTIONS). Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued.
7.1.4 Geriatrics
Geriatric patients and debilitated patients, or those with organic brain syndrome, have been found to be prone to CNS depression after even low doses of benzodiazepines. Therefore, medication should be initiated with very low initial doses in these patients, depending on the response of the patient, in order to avoid over sedation or neurological impairment.
As with any premedicant, extreme care must be used in administering ATIVAN to geriatric patients or very ill patients and to those with limited pulmonary reserve, because of the possibility that apnea and/or cardiac arrest may occur.
Clinical trials have shown that patients over the age of 50 years may have a more profound and prolonged sedation with intravenous lorazepam.
For geriatric patients and debilitated patients reduce the initial dose by approximately 50% and adjust the dosage as needed and tolerated.
Long-term use of ATIVAN should be avoided in geriatric patients or debilitated patients who may be more sensitive to benzodiazepines. There is an increased risk of cognitive impairment, delirium, falls, fractures, hospitalizations and motor vehicle accidents in these users. Enhanced monitoring is recommended in this population.
8 Adverse Reactions
8.1 Adverse Reaction Overview
The adverse reaction most frequently reported was drowsiness.
Reported adverse reactions (by system) are:
Body as a Whole
Angioedema, asthenia, muscle weakness, anaphylactic reactions, change in weight, drug withdrawal syndrome, hypersensitivity reactions, hyponatremia, hypothermia, SIADH;
Cardiovascular
Hypotension, lowering in blood pressure;
Digestive
Nausea, constipation, change in appetite, increase in bilirubin, jaundice, increase in liver transaminases, increase in alkaline phosphatase;
Hematological/Lymphatic
Agranulocytosis, pancytopenia, thrombocytopenia;
Nervous System and Special Senses (benzodiazepine effects on the CNS are dose dependent, with more severe CNS depression with higher doses)
Anterograde amnesia, drowsiness, fatigue, sedation, ataxia, confusion, depression, unmasking of depression, dizziness, change in libido, impotence, decreased orgasm, extrapyramidal symptoms, tremor, vertigo, visual disturbances (including diplopia, and blurred vision), dysarthria/slurred speech, headache, convulsions/seizures, amnesia, disinhibition, euphoria, coma, suicidal ideation/attempt, impaired attention/concentration, balance disorder, paradoxical reactions (including anxiety, agitation, excitation, hostility, aggression, rage, sleep disturbances/insomnia, sexual arousal, hallucinations), psychomotor agitation, drug abuse, drug dependence;
Respiratory
Respiratory depression, apnea, worsening of sleep apnea (the extent of respiratory depression with benzodiazepines is dose dependent - more severe depression at higher doses), worsening of obstructive pulmonary disease, and ear, nose and throat disturbances;
Skin
Allergic skin reactions, alopecia.
There is evidence that tolerance develops to the sedative effects of benzodiazepines.
Release of hostility and other paradoxical effects such as irritability and excitability, are known to occur with the use of benzodiazepines. Paradoxical reactions may be more likely to occur in children or the elderly. Should paradoxical reactions occur, use of the drug should be discontinued. In addition, hypotension, mental confusion, slurred speech, over sedation and abnormal liver and kidney function tests and hematocrit values have been reported with these drugs.
8.5 Post-Market Adverse Reactions
Injury, Poisoning and Procedural Complications
There have been reports of falls and fractures in benzodiazepine users due to adverse reactions such as sedation, dizziness and ataxia. The risk is increased in those taking concomitant sedatives (including alcoholic beverages), geriatric and debilitated patients.
Dependence/Withdrawal
Development of physical dependence and withdrawal following discontinuation of therapy has been observed with benzodiazepines such as ATIVAN. Severe and life-threatening symptoms have been reported. (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Addiction, Abuse and Misuse; 7 WARNINGS AND PRECAUTIONS, Dependence/Tolerance)
9 Drug Interactions
9.1 Serious Drug Interactions
Serious Drug Interactions
Concomitant use of ATIVAN and opioids may result in profound sedation, respiratory depression, coma and death.
- Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are not possible
- Limit dosage and durations to the minimum required
- Follow patients for signs and symptoms of respiratory depression and sedation
(see 3 WARNINGS AND PRECAUTIONS BOX, Risks from Concomitant use with Opioids)
9.2 Drug Interactions Overview
If lorazepam is to be used together with other drugs acting on the CNS, careful consideration should be given to the pharmacology of the agents to be employed because of the possible potentiation of drug effects. The benzodiazepines, including ATIVAN, produce additive CNS depressant effects when administered with other CNS depressants such as barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, anesthetics and alcohol.
9.3 Drug-Behavioural Interactions
Patients should be cautioned not to take alcohol during the administration of lorazepam because of the potentiation of effects that may occur.
ATIVAN produces depression of the CNS when administered with ethyl alcohol, phenothiazines, barbiturates, monoamine oxidase (MAO) inhibitors and other antidepressants. When scopolamine is used concomitantly with injectable lorazepam, an increased incidence of sedation, hallucinations and irrational behaviour has been observed.
9.4 Drug-Drug Interactions
The drugs listed below are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (ie. those identified as contraindicated).
Opioids: Due to additive CNS depressant effect, the concomitant use of benzodiazepines, including ATIVAN, and opioids increases the risk of profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations of concomitant use of benzodiazepines and opioids to the minimum required. Follow patients closely for respiratory depression and sedation (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX; 7 WARNINGS AND PRECAUTIONS – Risks from concomitant use of opioids and benzodiazepines).
Other drugs: There have been reports of apnea, coma, bradycardia, heart arrest, and death with the concomitant use of lorazepam injection and haloperidol.
Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, and ataxia.
Concurrent administration of lorazepam with valproate may result in increased plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage should be reduced to approximately 50% when co-administered 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 co-administered with probenecid.
Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam.
9.5 Drug-Food Interactions
Interactions with food have not been established.
9.6 Drug-Herb Interactions
Interactions with herbal products have not been established.
9.7 Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.
10 Clinical Pharmacology
10.1 Mechanism of Action
ATIVAN (lorazepam) is an active benzodiazepine with a depressant action on the central nervous system. It has anxiolytic and sedative properties which are of value in the symptomatic relief of pathologic anxiety in patients with anxiety disorders giving rise to significant functional disability but is not considered indicated in the management of trait anxiety.
In laboratory animals, lorazepam produces disinhibitory, sedative, anti-convulsant, muscle relaxant, ataxic and hypnotic effects.
ATIVAN (lorazepam) has also been shown to possess anticonvulsant activity.
Anterograde amnesia, a lack of recall of events during period of drug action, has been reported and appears to be dose-related.
10.2 Pharmacodynamics
Studies with lorazepam in rats demonstrated a decrease in treadmill avoidance without modifying the escape response, an increase in responding during the shock schedule in the conflict test, an increase in incorrect responses in a discrimination test, and a reduction of conditioned suppression if lorazepam was given prior to the fear conditioning trial, while increasing conditioned suppression, if given prior to re-testing. These effects were observed at doses from 0.05 to 20 mg/kg i.p. In some of the tests, diazepam was also used with similar results obtained at approximately 2-5 times the lorazepam dose.
Lorazepam was the most potent of several benzodiazepines tested in affecting state-dependent learning in trained, hungry rats rewarded with sweetened milk and conditioned to simple fear responses by mild electric shock. While 70-75% inhibition of conditioned fear was achieved with intraperitoneal doses of 0.9 mg/kg of lorazepam on the training day, 2.7 mg/kg of diazepam and 5 mg/kg of either chlordiazepoxide or oxazepam were required to obtain similar results. Consistent with state-dependent learning interpretations, a second injection of lorazepam administered to rats just prior to being tested for fear retention fully reinstated the conditioned suppression response.
Daily intraperitoneal injections of lorazepam, diazepam, oxazepam, chlordiazepoxide, scopolamine, or amobarbital, after initially interfering with feeding behaviour, later facilitated it. Following fear conditioning of the animals, all of the drugs, with the exception of scopolamine, increased conditioned suppression in the retention test. These repeated dose experiments, which permit tolerance of depressant side effects to develop, make it unlikely that benzodiazepines or amobarbital increase conditioned suppression retention through some depressant side effect.
In rats, fear-conditioned by electric shocks of different intensities, lorazepam increased retention-test drinking latencies of strongly shocked rats more than it did those of rats given shocks of intermediate or weak intensities.
In mice, lorazepam prevented pentylenetetrazol-induced convulsions at low doses (ED50-0.07 mg/kg p.o.), while much higher doses (0.5-5.0 mg/kg p.o.) were required to raise the threshold to electroshock-induced convulsions. It was demonstrated that lorazepam was more potent than diazepam in antagonizing pentylenetetrazol-induced convulsions by all three routes tested: oral, intraperitoneal, and intravenous. Lorazepam also inhibited the stimulation caused by morphine. Both lorazepam and clonazepam had ED50s for the antagonism of convulsions of less than 1 mg/kg when they were given intravenously or orally only 1 minute before the pentylenetetrazol challenge.
Observations of monkeys provided strong evidence of the sedative action of lorazepam. Here, relatively high doses of lorazepam caused brief initial depression followed by long periods of obvious sedation. The behaviour of cats and mice, after receiving lorazepam supported these findings. In mice, it was shown that lorazepam is a more potent sedative than diazepam or flurazepam.
Its ability to inhibit foot shock induced fighting between mice, together with reactions of rats and squirrel monkeys in a series of conflict tests considered specific predictors of anti-anxiety activity, confirmed the anxiolytic potential of lorazepam.
The general depressant effects of repeated dosings of lorazepam in rats diminished rapidly while its anticonflict action remained, findings suggesting that while the anti-anxiety effects of lorazepam endure, any behaviour disruption is transitory.
Doses of 5 to 50 mg/kg I.V. caused ataxia and obvious CNS depression in rhesus monkeys, lasting for over 5 hours at the highest dose. Suppression of the linguomandibular reflex was demonstrated in anaesthetized cats suggesting a central muscle-relaxant effect of lorazepam in this species. Higher doses, however, were required than with diazepam to produce significant reflex inhibition.
Using suppression of linguomandibular reflexes in cats as a measure of centrally mediated muscle relaxation, it was demonstrated that intravenous doses of 0.25 to 2 mg/kg of lorazepam were active in a dose-related manner, that the patellar reflex was not suppressed indicated a preferential effect on polysynaptic pathways.
Studies on the cardiovascular system in anaesthetized animals demonstrated that lorazepam, at a dose of 0.1 mg/kg, given by intraperitoneal injection had little effect on either blood pressure or heart rate. Second injections of 0.9 mg/kg one hour later caused some depression of cardiovascular parameters of anaesthetized cats and dogs. Doses greater than 0.9 mg/kg resulted in an average decrease of approximately 40% in both blood pressure and heart rate. Electrocardiograms taken near the conclusion of a 33-34 day study in which beagle dogs received daily intramuscular injections of lorazepam showed only slight increases in the heart rates of both vehicle control and drug-treated animals.
10.3 Pharmacokinetics
The serum half-life of lorazepam ranges between 12 to 15 hours, while that of the conjugate varied between 16 to 20 hours.
Absorption
Lorazepam is rapidly absorbed after oral administration, with mean peak plasma concentrations of free lorazepam at 2hours (range between 1-6 hours). Following intravenous administration, peak plasma levels are reached within minutes, whereas following administration by the intramuscular route, peak plasma levels occur between 60 to 90 minutes. After sublingual administration, peak plasma levels occur at 60 minutes. By the intramuscular route, the absorption half-life values of lorazepam average 12 and 19 minutes, whereas by the oral route, there is an additional lag period averaging 15 and 17 minutes. Bioavailability was shown to be identical by all routes of administration.
Lorazepam is rapidly conjugated to a glucuronide which has no demonstrable psychopharmacological activity and is excreted mainly in the urine. Very small amounts of other metabolites and their conjugates have been isolated from urine and plasma.
Distribution:
Except for the organs of absorption and excretion, tissue distribution of 14C-lorazepam in rats was nearly uniform.
Metabolism:
Metabolic studies in mice, rats, cats, dogs and miniature swine were conducted on the absorption, excretion, tissue distribution and biotransformation of lorazepam. Both 14C-labelled and unlabelled drug was used. The most important finding was the conjugation of lorazepam with glucuronic acid in all investigated species. Lorazepam glucuronide, essentially inactive as an anti-anxiety agent, accounted for most of the drug-related urinary excretion products in all species except the rat in which, in addition to glucuronide formation, more extensive biotransformation took place.
Elimination
Most of the drug (88%) is excreted in the urine, with 75% excreted as the glucuronide. At the clinically relevant concentrations, approximately 85% of lorazepam is bound to plasma proteins.
Maximum concentrations of unchanged lorazepam in whole blood and plasma of rats occurred one-half to one hour after oral drug administration, and these concentrations declined to low levels within 24 hours. In dogs and miniature swine, concentrations of orally administered lorazepam peaked and declined rapidly, but they consisted principally of lorazepam glucuronide. These findings correlated with the rapid elimination observed in dogs administered lorazepam intravenously when no free drug was detected in plasma six hours later, and the half-life was estimated to be 1.6 hours. The major route of lorazepam excretion for the dog and the miniature swine is by the kidneys. Biliary excretion has been demonstrated in the rat.
Maximum concentrations of unchanged lorazepam in whole blood and plasma of rats occurred one-half to one hour after oral drug administration, and these concentrations declined to low levels within 24 hours. In dogs and miniature swine, concentrations of orally administered lorazepam peaked and declined rapidly, but they consisted principally of lorazepam glucuronide. These findings correlated with the rapid elimination observed in dogs administered lorazepam intravenously when no free drug was detected in plasma six hours later, and the half-life was estimated to be 1.6 hours. The major route of lorazepam excretion for the dog and the miniature swine is by the kidneys. Biliary excretion has been demonstrated in the rat.
Species differences in urinary excretion patterns were investigated qualitatively in the mouse, rat, cat, dog, and miniature swine. The major urinary excretion product was the glucuronide conjugate of lorazepam. In dogs, the pattern of biotransformation of lorazepam seemed independent of dose; in rats, it appeared dose-dependent and produced significant amounts of several metabolites rather than the predominance of glucuronide found in other species, including the human. No sex differences were noted in the urinary excretion patterns of the several species tested.Peak urinary excretion was noted at 2-6 hours and total recovery in urine and feces over 48 hours was as high as 100% in some species.
Special Populations and Conditions
The special populations and conditions pharmacokinetics data on which the original indication was authorized is not available.
11 Storage, Stability And Disposal
Store at controlled room temperature (15 - 30°C).
Sublingual tablets should also be protected from light.
12 Special Handling Instructions
None
Control #: 267182
December 28, 2022
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