TEVA-LORAZEPAM TABLET

Canada - English - Health Canada

Buy It Now

Active ingredient:
LORAZEPAM
Available from:
TEVA CANADA LIMITED
ATC code:
N05BA06
INN (International Name):
LORAZEPAM
Dosage:
0.5MG
Pharmaceutical form:
TABLET
Composition:
LORAZEPAM 0.5MG
Administration route:
ORAL
Units in package:
100/500/1000
Prescription type:
Targeted (CDSA IV)
Therapeutic area:
BENZODIAZEPINES
Product summary:
Active ingredient group (AIG) number: 0110731003; AHFS: 28:24.08
Authorization status:
APPROVED
Authorization number:
00711101
Authorization date:
2013-12-06

Documents in other languages

PRESCRIBING INFORMATION

TEVA-LORAZEPAM

Lorazepam Tablets, Teva Standard

0.5 mg, 1 mg, 2 mg

Anxiolytic-Sedative

Teva Canada Limited

30 Novopharm Court

Toronto, Ontario

Canada M1B 2K9

www.tevacanada.com

Date of Revision:

September 30, 2019

Control No.: 231836

TABLE OF CONTENTS

ACTION ............................................................................................................................................. 3

INDICATIONS AND CLINICAL USE............................................................................................. 4

CONTRAINDICATIONS .................................................................................................................. 4

WARNINGS ....................................................................................................................................... 4

PRECAUTIONS ................................................................................................................................. 7

DRUG INTERACTIONS ................................................................................................................... 8

ADVERSE REACTIONS ................................................................................................................ 10

SYMPTOMS AND TREATMENT OF OVERDOSAGE ............................................................... 11

DOSAGE AND ADMINISTRATION ............................................................................................. 12

AVAILABILITY OF DOSAGE FORMS ........................................................................................ 13

PHARMACOLOGY ........................................................................................................................ 14

TOXICOLOGY ................................................................................................................................ 18

REFERENCES ................................................................................................................................. 22

PART III: CONSUMER INFORMATION ..................................................................................... 25

ACTION

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS

Concomitant use of TEVA-LORAZEPAM and opioids may result in profound sedation,

respiratory depression, coma, and death (see WARNINGS-Risks from concomitant use of

opioids and benzodiazepines).

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.

TEVA-LORAZEPAM (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.

Lorazepam has also been shown to possess anticonvulsant activity.

Lorazepam is rapidly absorbed after oral administration, with mean peak plasma

concentrations of free lorazepam at 2 hours (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.

The serum half-life of lorazepam ranges between 12 to 15 hours, while that of the

conjugate varied between 16 to 20 hours. 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.

Anterograde amnesia, a lack of recall of events during period of drug action, has been

reported and appears to be dose-related.

INDICATIONS AND CLINICAL USE

TEVA-LORAZEPAM (lorazepam) is useful for the short-term relief of manifestations of

excessive anxiety in patients with anxiety neurosis.

Anxiety and tension associated with the stresses of everyday life usually do not require

treatment with anxiolytic drugs.

CONTRAINDICATIONS

TEVA-LORAZEPAM (lorazepam) is contraindicated in patients with myasthenia gravis or

acute narrow angle glaucoma, and in those with known hypersensitivity to benzodiazepines

WARNINGS

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.

TEVA-LORAZEPAM (lorazepam) is not recommended for the use in depressive neurosis

or in psychotic reactions. Because of the lack of sufficient clinical experience, lorazepam is

not recommended for use in patients less than 18 years of age (see PRECAUTIONS).

Since TEVA-LORAZEPAM has a central nervous system depressant effect, patients should

be advised against the simultaneous use of other CNS depressant drugs. Patients should

also be cautioned not to take alcohol during the administration of lorazepam because of the

potentiation of effects that may occur.

Excessive sedation has been observed with lorazepam at standard therapeutic doses.

Therefore, patients on TEVA-LORAZEPAM should be warned against engaging in

hazardous activities requiring mental alertness and motor coordination, such as operating

dangerous machinery or driving motor vehicles.

As with any premedicant, extreme care must be used in administering TEVA-

LORAZEPAM to elderly 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.

There is no evidence to support the use of lorazepam in coma, shock or acute alcohol

intoxication at this time. When TEVA-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.

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.

Risks from concomitant use of opioids and benzodiazepines:

Concomitant use of benzodiazepines, including TEVA-LORAZEPAM, 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 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 opioid analgesics.

If a decision is made to prescribe TEVA-LORAZEPAM 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 TEVA-LORAZEPAM

than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid

analgesic is initiated in a patient already taking TEVA-LORAZEPAM, 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 DRUG

INTERACTIONS).

Advise both patients and caregivers about the risks of respiratory depression and sedation

when TEVA-LORAZEPAM 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.

Use in Pregnancy: lorazepam 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 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. There are insufficient data regarding obstetrical

safety of parenteral lorazepam, including use in caesarean section. Such use, therefore, is

not recommended.

Use in Nursing Mothers: Lorazepam has been detected in human breast milk; therefore it

should not be administered to breast-feeding 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).

Use in Children: Lorazepam is not intended for use in children under 18 years of age.

The safety and effectiveness of lorazepam in children less than 18 years of age has not

been established (see TOXICOLOGY).

PRECAUTIONS

Lorazepam should be used with caution in patients with compromised respiratory function

(e.g., COPD, sleep apnea syndrome).

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.

Paradoxical reactions have been occasionally reported during benzodiazepine use (See

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.

Use in the Elderly: Elderly 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.

For elderly and debilitated patients reduce the initial dose by approximately 50% and adjust

the dosage as needed and tolerated.

Dependence Liability: TEVA-LORAZEPAM (lorazepam) should not be administered to

individuals prone to drug abuse. Lorazepam may have abuse potential, especially in

patients with a history of drug and/or alcohol abuse.

Caution

should

observed

patients

considered

have

potential

psychological dependence. It is suggested that the drug should be withdrawn gradually if

it has been used in high dosage.

The use of benzodiazepines, including lorazepam, may lead to physical and psychological

dependence. The risk of dependence increases with higher doses and longer term use and is

further increased in patients with a history of alcoholism or drug abuse or in patients with

significant personality disorders. The dependence potential is reduced when lorazepam is

used at the appropriate dose for short-term treatment. In general, benzodiazepines should be

prescribed for short periods only (e.g., 2-4 weeks). Continuous long-term use of lorazepam is

not recommended.

Use in Mental and Emotional Disorders: TEVA-LORAZEPAM (lorazepam) 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 TEVA-LORAZEPAM, it should be recognized that suicidal tendencies may

be present and that protective measures may be required.

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

TEVA-LORAZEPAM be used in patients with mild to moderate hepatic or renal disease. In

patients for whom prolonged therapy with lorazepam 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.

DRUG INTERACTIONS

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 lorazepam 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.

Opioids

Due to additive CNS depressant effect, the concomitant use of benzodiazepines, including

TEVA-LORAZEPAM, 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 WARNINGS- Risks from concomitant

use of opioids and benzodiazepines).

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.

Lorazepam produces depression of the CNS when administered with ethyl alcohol,

phenothiazines, barbiturates, 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.

ADVERSE REACTIONS

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, 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;

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.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

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.

DOSAGE AND ADMINISTRATION

DOSAGE: The dosage and duration of therapy of TEVA-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 lowest effective dose of TEVA-LORAZEPAM should be prescribed for the shortest

duration possible. The risk of withdrawal and rebound phenomena is greater after abrupt

discontinuation; therefore the drug should be discontinued gradually. Withdrawal symptoms

(e.g., rebound insomnia) can appear following cessation of recommended doses after as little

as one week of therapy. Abrupt discontinuation of lorazepam should be avoided and a

gradual, dose-tapering schedule followed after extended therapy.

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 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.

Generalized Anxiety Disorder: The recommended initial adult daily oral dosage is 2 mg in

divided doses of 0.5, 0.5 and 1 mg, 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 3 mg. 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 elderly 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.

AVAILABILITY OF DOSAGE FORMS

Small, round, white, flat with bevelled-edge, compressed tablets. Engraved N on one side, 0.5

on the reverse. Each TEVA-LORAZEPAM tablet contains lorazepam 0.5 mg. Available in

bottles of 100 and 1000.

Small, white, capsule shaped, flat with beveled-edge, compressed tablets. Engraved N, vertical

scoreline and 1 on one side, plain on the reverse. Each TEVA-LORAZEPAM tablet contains

lorazepam 1 mg. Available in bottles of 100, 1000 and 3000 and in unit dose packages of 100.

White, oval-shaped, flat with beveled-edge, compressed tablets. Engraved N, vertical scoreline

and 2 on one side, plain on the reverse. Each TEVA-LORAZEPAM tablet contains lorazepam

2 mg. Available in bottles of 100 and 1000 and in unit dose packages of 100.

Bottles: Store at controlled room temperature (15°C - 30 °C).

Unite Dose (blister): Store between 15°C -25°C.

Non-Medicinal Ingredients:

Each 0.5 mg, 1 mg, 2 mg TEVA-LORAZEPAM tablet contains:

Colloidal Silicon Dioxide, Magnesium Stearate, Microcrystalline Cellulose, Sodium Lauryl

Sulfate and Starch.

PHARMACOLOGY

TEVA-LORAZEPAM is chemically 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-

2H-1, 4- benzodiazepin-2-one and has the following structural formula:

Figure 1: Lorazapam Structural Formula

Lorazepam is a benzodiazepine with CNS depressant properties. In laboratory animals, it

produces disinhibitory, sedative, anti- convulsant, muscle relaxant, ataxic and hypnotic

effects.

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 (ED

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 ED

s 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.

In anticipation of lorazepam being used concomitantly with other therapeutic agents in a

variety of clinical situations, drug interaction studies were undertaken. Lorazepam was

without effect on the LD

of morphine in rats. Although the oral LD

of lorazepam in

mice was not modified by phenelzine, the depressor effect of intravenous lorazepam or

diazepam in the presence of phenelzine, was increased in rats. In common with other

anxiolytic-sedatives, oral lorazepam in mice reduced the amount of I.V. thiopental required

for hypnosis and respiratory arrest.

Oral doses of lorazepam administered daily for 59 days to beagle dogs did not alter the

anticoagulant activity of bishydroxycoumarin. In decerebrate cats, the intensity and duration

of the skeletal neuromuscular blocking action of gallamine and suxamethonium were

unaffected by intravenous doses of either diazepam or lorazepam.

The drug dependency potential of lorazepam (10 mg/kg), diazepam (5 mg/kg) and

chlordiazepoxide (20 mg/kg) by several routes of administration was evaluated in

normal, barbital-dependent and withdrawn rhesus monkeys. Like chlordiazepoxide

and diazepam, lorazepam suppressed signs of barbital withdrawal. In long-term

toxicity studies, convulsions were noted, at the high-dose levels, particularly following

withdrawal of lorazepam.

The irritant potential of injectable lorazepam was compared with that of diazepam in mice

and rabbits. While the degrees of irritation produced by either compound varied with the

routes of administration, it appeared that the experimental vehicles were the principle

cause of irritation. The degree of hemolytic potential of lorazepam in an experimental

vehicle varied from mild to moderate in rabbit blood, and slight to mild in human or dog

blood.

Metabolic studies in mice, rats, cats, dogs and miniature swine were conducted on the

absorption, excretion, tissue distribution and biotransformation of lorazepam. Both

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.

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.

Except for the organs of absorption and excretion, tissue distribution of

C-lorazepam

in rats was nearly uniform.

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.

TOXICOLOGY

Acute Toxicity: Oral. LD

s ranged from 1850-5010 mg/kg in mice to 5000 mg/kg in rats

and 2000 mg/kg in dogs. The intraperitoneal LD

s were 700 mg/kg in rats and mice. In

newborn rats and mice, intragastric LD

values were 200 and 250 mg/kg respectively.

Signs exhibited during acute toxicity testing included moderate to marked sedation,

shortness of breath, paralysis of hind legs, loss of righting reflex and convulsions. Acute

respiratory depression was noted as the mode of death.

Injectable. The acute toxicity of lorazepam in adult mice and rats were determined to be:

In beagle dogs, the approximate LD

for intravenous lorazepam was 50 mg/kg (equivalent to

10 mL/kg). The highest intramuscular dose of lorazepam that, because of its volume, could be

given to dogs was 25 mg/kg (equivalent to 5 mL/kg). The toxicity of injectable lorazepam in

all three species seemed due almost entirely to the vehicle employed.

Long-Term Toxicity: Oral. Lorazepam was administered in the diet to rats in a number of

studies extending for periods of 4 to 82 weeks at doses ranging from 14.5 to 400 mg/kg/day.

In the long-term studies, decreased food consumption and body weight gain were observed at

the higher dose levels, while at lower dose levels weight gain tended to be increased relative

to controls. Transient, dose-related sedation and ataxia also occurred, and convulsions were

noted, particularly following drug withdrawal. The only gross pathological finding was

esophageal dilatation, which was observed in a number of animals at different dose levels.

This condition also occurred with diazepam, and the significance of this finding is at present

unknown.

Increased liver, kidney, thyroid, adrenal and testicular weights, as well as centrilobular

hypertrophy of the liver, cloudy swelling and loss of glycogen were observed in drug-treated

animals. At the highest dose levels, changes in the nuclei of the hypertrophied liver cells

also occurred. In one study, the colloid follicles of the thyroid were lined with tall cells and

were reported to be increased in a dose-related manner. Effects on blood chemistry included

SPECIES

Mouse

ROUTE

i.m.

mg/kg

Mouse

i.m.

i.p.

i.v.

i.m.

i.p.

increases in serum protein and cholesterase levels and a decrease in serum alkaline

phosphatase. These changes were observed mostly at the higher dose levels and were more

marked in females.

Three oral studies were conducted in dogs, ranging from 6 to 52 weeks in duration at doses

of up to 480 mg/kg/day. A high incidence of emesis occurred in the early stages of the

studies. Most drug treated dogs exhibited the following signs: sedation, ataxia, tremors,

restlessness, excitement, apprehension, salivation, panting, vocalization, muscle weakness

and depression; of these only sedation persisted. Polydipsia was also observed. There were

some increases in spleen, liver and testicular weight, and, at the highest dose, serum alkaline

phosphatase and hematocrit values were elevated. Increased platelet and cholesterol values

were also noted in the long-term study.

Injectable. In two studies in adult rats, lorazepam was administered either intravenously for

ten days or intramuscularly for 33 to 37 days. Food consumption and body weight gain

were little affected.

Most animals were sedated to some extent, and even ataxic at the high doses. Statistically

significant differences to hematologic values between treated and control animals of both

studies were within normal limits. With the possible exception of decreases in serum glucose

in the second study, allserum chemical differences were small and considered biologically

unimportant. Ophthalmoscope examinations made in both studies revealed no ocular

abnormalities.

Some organ weights of lorazepam-treated animals differed significantly from those of

control animals, but there was no consistent pattern to the variations.

Histopathologic examinations at the end of both studies revealed marked tissue reactions at

the injection sites of rats treated with either lorazepam or vehicle alone. The only other

pathological change thought to be related to treatment was an unusual degree of

extramedullary splenic hematopoiesis, a condition confined chiefly to high-dose animals of

Study 2. There were no accompanying changes in bone marrow or lymphoid tissues.

Purebred beagle dogs received daily intramuscular injections of 2.5, 5.0 or 10.0 mg/kg of

lorazepam for 33-34 days. Their behaviour was only mildly and occasionally affected;

appetite and mean body weight changes were similar in treated and untreated dogs. The drug-

treated animals drank more water. There were episodes of emesis, and occasionally some

stools were loose. Injection site sores developed on drug-treated and vehicle control dogs.

Electrocardiograms taken near the study's conclusion showed slight increases in heart rate of

vehicle control and lorazepam-treated animals. Alterations in several hematologic parameters

in lorazepam-treated and vehicle control dogs were attributed to loss of blood and

inflammatory reactions at injection sites. Statistical analysis of group mean blood chemical

values showed several significant differences in mid and high-dose lorazepam dogs and those

given the vehicle only. With the possible exception of elevated cholesterol, SGPT, and SGOT

values, these differences were small and believed to be of no biological importance. The

elevated SGOT levels were attributed to injection site inflammation. While some changes

were suggestive of liver involvement, no histological alterations to that organ were discovered.

Marked inflammatory injection site reactions were found on all dogs treated with lorazepam or

its vehicle. Splenic hematopoiesis occurred in varying degrees among drug-treated and

vehicle control animals. Hypercellularity of the bone marrow was discovered in four

lorazepam-treated dogs and two vehicle control animals. It is likely this resulted from

injection site stress and blood loss.

Reproductive Studies: Oral. A number of reproductive studies, covering various stages of

the reproductive cycle, were carried out in rats, rabbits and mice. Lorazepam was

administered orally in doses of up to 50 mg/kg/day. The observed effects in drug-treated

groups of all three species included decreased maternal weight gain, increased resorptions,

increased incidence of complete litter loss, decreased litter size, increased number of

stillborn, increased neonatal mortality and decreased fetal body weight. Major and minor

malformations, including cleft palate, hindlimb malrotation, extra 13th ribs, gastroschisis

and major skull deficiency, were noted in rabbit and mouse experiments; some of these were

qualitatively similar and/or dose related, and possibly drug induced.

Developmental Neurotoxicity: Nonclinical research has shown that administration of

anesthetic and sedation drugs that block N-methyl-D-aspartate (NDMA) receptors and/or

potentiate gamma-aminobutyric acid (GABA) activity can increase neuronal cell death in the

brain and result in long term deficits in cognition and behavior of juvenile animals when

administered during the period of peak brain development. Based on comparisons across

nonclinical species, the window of vulnerability of the brain to these effects is believed to

correlate with human exposures in the third trimester of pregnancy through the first year of

life, but may extend to approximately 3 years of age. While there is limited information of

this effect with lorazepam, since the mechanism of action includes potentiation of GABA

activity, a similar effect may occur. The relevance of these nonclinical findings to human use

is unknown.

Injectable. Lorazepam, intravenously administered, was studied in rats and rabbits for its

possible impact on reproduction and fetal development. Injectable lorazepam was associated

to some extent with the number of resorptions, litter sizes and weights in both species, but

these effects were neither consistent nor dose related.

In rats and rabbits, injectable lorazepam was not teratogenic.

IMPORTANT: PLEASE READ

REFERENCES

Alps BJ, Harry TVA, Southgate PJ. The pharmacology of lorazepam, a broad-spectrum

tranquillizer. Curr. Med. Res. Opin. 1975; 1:239-261.

Ban TA. ECEDEU Reports. Psychopharmacol. Bull., 1973; 9:69-71.

Brunaud M, Rocand J. Une nouvelle benzodiazepine, le lorazepam mise au point

pharmacologique. Agressologie. 1972; 13:363-375.

Caille G, Lacasse Y, Vezina M, Porter R, Shaar S, Darke A. A novel route for benzodiazepine

administration: a sublingual formulation of lorazepam. In: Manzo, L., et al., eds. Advances in

neurotoxicology. Pergamon Press, 1980.

Calixto N, De Costa Maia JA. Influence of lorazepam on ocular pressure in patients with

glaucoma. Curr. Ther. Res. 1975; 17:156-160.

Coates H. Lorazepam and diazepam in severe neurotic illness. Curr. Med. Res. Opin.

1972; 1:74-77.

De Buck R. Clinical experience with lorazepam in the treatment of neurotic patients.

Curr. Med. Res. Opin. 1973; 1:291-295.

Denaut M, Yernault JC, De Coster A. Double blind comparison of the respiratory effects of

parenteral lorazepam and diazepam in patients with chronic obstructive lung disease. Curr. Med.

Res. Opin. 1975; 2:611-615.

Dundee JW, George KA. Relative amnesic actions of diazepam, flunitrazepam and

lorazepam in man. Br. J. Clin. Pharmacol. 1977; 4:45-50.

Dundee JW, Johnston HML, Gray RC. Lorazepam as a sedative-amnesic in an intensive care

unit. Curr. Med. Res. Opin. 1976; 4:290-295.

Eaves D, Jain VK, Swinson RP. A double blind controlled trial of lorazepam and

diazepam in the treatment of anxiety. Curr Med Res and Opinion 1973; 1:265-268.

Elliot HW. Metabolism of lorazepam. Br. J. Anaesth. 1976; 48:1017-1023.

Gale G, Galloon S. Lorazepam as a premedication. Can. Anaesth. Soc. J. 1976; 23:22-

Galloon S, Gale GD, Lancee WJ. Comparison of lorazepam and diazepam as

Premedicants. Br. J. Anaesth. 1977; 49:1256-1269.

Gasser CJ, Kaufman RD, Bellville WJ. Respiratory effects of lorazepam, pentobarbital and

IMPORTANT: PLEASE READ

pentazocine. Clin. Pharmacol. Ther. 1975; 18:170-174.

Gluckman MI. Pharmacology of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-

2H-1,4-benzodiazepin-2-one (lorazepam; WY-4036). Arzneimittelforsch. 1971;

21:1049-1055.

Goldberg HL, Finnerty RJ, Cole JO. A study of anti-anxiety effects of WY-4036.

Compr. Psychiatry. 1974; 15:95-200.

Greenblatt DJ, et al.: Clinical pharmacokinetics of lorazepam. Clin. Pharmacol. Ther.

1976; 20:329-339.

Haider I. Evaluation of a new tranquillizer - WY-4036 in the treatment of anxiety. Br. J.

Psychiatry. 1971; 119:597-598.

Haider I. A comparative trial of lorazepam and diazepam. Brit. J. Psychiatry. 1971;

119:599-600.

Hedges A, Turner P, Harry TVA. Preliminary studies on central effects of lorazepam a new

benzodiazepine. J. Clin. Pharmacol. 1971; 2:423-427.

Heisterkamp DV, Cohen PJ. The effect of intravenous premedication with lorazepam

(Ativan), pentobarbitone or diazepam on recall. Br. J. Anaesth. 1975; 47:79-81.

Knapp RB, Fierro L. Evaluation of the cardiopulmonary safety and effects of lorazepam as a

premedicant. Anesth. Analg. 1974; 53:122-124.

Knowles JA, Comer WH, Ruelius HW. Disposition of 7-chloro-5-(o- chlorophenyl)-1,3-

dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one (lorazepam) in humans. Arzneimittelforsch.

1971; 21:1055-1059.

Nanivadekar AS, Wig NN, Khorana AB, Master RS, Kulkarni SS. A multicenter

investigation of lorazepam in anxiety neurosis. Curr. Ther. Res. 1973; 15:432-439.

Owen G, Hatfield GK, Pollock JJ, Steinberg AJ, Tucker WE, Agersborg HPK (Jr).

Toxicity studies of lorazepam, a new benzodiazepine, in animals. Arzneimittelforsch.

1971; 21:1065-1073.

Rickels K, Case WG, Csanalosi I, Pereira-Ogan JA, Parish L, Bell PJ. Lorazepam in anxiety:

a controlled study. J. Int. Med. Res. 1974; 2:20-25.

Saxena BM, Singh AN, Nelson HL, Mahutte G: Clinical experience with oral and

parenteral lorazepam. Curr. Ther. Res. 1979; 25:1- 15.

Schillings RT, Shader SR, Ruelius HW. Urinary Metabolites of 7-chloro-5- (o-

chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one (lorazepam) in humans

and four animal species. Arzneimittelforsch. 1971; 21:1059-1065.

Singh AN, Saxena B. A Comparison of lorazepam, diazepam and placebo in the

IMPORTANT: PLEASE READ

treatment of anxiety states. Curr. Ther. Res. 1974; 16:149-162.

Stein L, Berger BD. Psychopharmacology of 7-chloro-5-(o-chlorophenyl)-1, 3-dihydro-3-hydroxy-

1,4-benzodiazepin-2-one (lorazepam) in squirrel, monkey and rat.

Arzneimittelforsch. 1971; 21:1072-1078.

Ativan Product Monograph dated January 31, 2019, Control #221513.

IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

TEVA-LORAZEPAM

Oral Tablets

This leaflet is part III of a three-part "Product

Monograph" published for TEVA-

LORAZEPAM and is designed specifically for

Consumers.

Please read this information before you start to take

your medicine. Keep this leaflet until you have

finished all your tablets, as you may need to read it

again. If you are helping someone else to take

TEVA-LORAZEPAM, read this leaflet before you

give the first tablet.

This leaflet is a summary and will not tell you

everything about TEVA-LORAZEPAM. Contact

your doctor or pharmacist if you have any

questions about the drug.

What the medication is used for:

TEVA-LORAZEPAM is useful for the short-term

relief of manifestations of severe anxiety in people

with anxiety neurosis.

TEVA-LORAZEPAM is not recommended for mild

to moderate anxiety and tension associated with the

stresses of everyday life.

What it does:

TEVA-LORAZEPAM is a benzodiazepine with

sedative properties which help in the treatment of

anxiety.

When it should not be used:

If you are allergic to the group of medicines

known as benzodiazepines (examples:

diazepam, clonazepam, chlordiazepoxide,

bromazepam, or flurazepam)

If you are allergic to any of the ingredients it

contains (see ‘What the nonmedicinal

ingredients are’)

If you have myasthenia gravis, a chronic disease

characterized by weakness of the skeletal

muscles.

If you have acute narrow angle glaucoma

disease

which

causes

progressive vision loss).

What the medicinal ingredient is:

Lorazepam.

What the nonmedicinal ingredients are:

TEVA-LORAZEPAM oral tablets: Each 0.5 mg, 1

mg, 2 mg TEVA-LORAZEPAM oral tablet

contains: Colloidal Silicon Dioxide, Magnesium

Stearate, Microcrystalline Cellulose, Sodium Lauryl

Sulfate and Starch.

What dosage forms it comes in:

0.5, 1 and 2mg Oral Tablets.

Serious Warnings and Precautions

Taking TEVA-LORAZEPAM with opioid

medicines can cause severe drowsiness, breathing

problems, coma, and death.

Severe anaphylactic/anaphylactoid allergic

reactions have been reported with the use of

benzodiazepines. Cases of angioedema

(swelling inside the mouth and throat)

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

(difficult respiration), 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 re-start the drug.

TEVA-LORAZEPAM may affect your ability to

be alert. Driving, operating machinery and other

hazardous activities should therefore be avoided

altogether or at least during the first few days of

treatment. This effect of TEVA-LORAZEPAM

may be made worse if you take alcoholic drinks.

If your doctor has increased your dose or if you

have changed the timings of when you take your

medication this may also modify your reactions.

You must not consume alcohol or other drugs

that affect the central nervous system while

taking TEVA-LORAZEPAM (see

INTERACTIONS WITH THIS

MEDICATION below).

Benzodiazepines such as TEVA-

LORAZEPAM have produced dependence

(addiction) and withdrawal symptoms can occur

when treatment is stopped suddenly. The risk of

dependence (addiction) increases with higher

ABOUT THIS MEDICATION

WARNINGS AND PRECAUTIONS

IMPORTANT: PLEASE READ

doses and longer duration of treatment.

Always contact your doctor before stopping or

reducing your dosage of TEVA-LORAZEPAM,

as suddenly stopping treatment or a large decrease

in dose can cause withdrawal symptoms (See

Withdrawal-related side effects in the section

SIDE EFFECTS AND WHAT TO DO

ABOUT THEM below).

An increased risk of falls and fractures has been

reported in elderly people who take

benzodiazepines such as TEVA-LORAZEPAM.

Memory loss may occur when TEVA-

LORAZEPAM is used at therapeutic doses.

A variety of abnormal thinking and behaviour

changes may occur when you use a

benzodiazepine, including aggressiveness,

extroversion, confusion, strange behaviour,

restlessness, illusions, hallucinations, feeling like

you are not yourself, worsening of insomnia or

worsening of depression including suicidal

thinking. It is rarely clear whether such symptoms

are caused by the medication, by an illness that

was present before the medication

was used or are simply spontaneous happenings. If

you develop any unusual or disturbing thoughts or

behavior while using TEVA-

LORAZEPAM,discuss the matter immediately

with your doctor.

TEVA-LORAZEPAM is not recommended for

use in depressive neurosis or in psychotic

reactions.

Certain benzodiazepines have been linked to

birth defects when taken during the early months

of pregnancy. In addition, benzodiazepines

taken during the last weeks of pregnancy have

been known to sedate the baby and may also cause

withdrawal symptoms after birth. Do not take this

medicine if you are pregnant, or might become

pregnant, unless advised by your doctor. Contact

your doctor if you think you may be pregnant, or

are intending to become pregnant.

TEVA-LORAZEPAM passes into breast milk.

Therefore, if you are breast feeding, this

medicine should be avoided. Your doctor will

discuss this with you.

BEFORE you use talk to your doctor or

pharmacist if:

You have lung disease or breathing problems

(e.g. chronic obstructive pulmonary disease

(COPD), sleep apnea syndrome)

You have a history of depression, suicide

attempts or psychosis

You regularly drink alcohol or use recreational

drugs or have a history of dependence

/addiction to alcohol or drugs.

You have liver disease

You have kidney disease

You are pregnant or plan on becoming

pregnant

You are breastfeeding

INTERACTIONS WITH THIS MEDICATION

INTERACTIONS WITH THIS MEDICATION

Tell

your

doctor

taking

other

medicines, including medicines you can buy without a

prescription and herbal products.

Drugs that may interact with TEVA-LORAZEPAM

include:

barbiturates

antipsychotics

sedative/hypnotics (sleeping pills)

anxiolytics

antidepressants

antipsychotics (including Haloperidol,

Clozapine)

narcotic analgesics (pain relievers)

(opioids)

(see Serious Warnings and Precautions box)

sedative antihistamines (allergy

medications)

anticonvulsants (including Valproate)

anesthetics

Probenecid (to reduce uric acid levels)

Theophylline or aminophylline (respiratory

treatments)

alcohol

Do not take TEVA-LORAZEPAM if you drink

alcohol.

Do not use TEVA-LORAZEPAM along with other

medications without first discussing this with your

doctor.

PROPER USE OF THIS MEDICATION

Always take the tablets exactly as your doctor tells you

to. Your doctor will prescribe a suitable dose for

you. The dose your doctor prescribes will depend on

your illness and how you respond to the medicine. The

table below shows the different doses that your doctor

may prescribe according to your illness.

Usual Daily Dose

Generalized anxiety

disorders

0.5-2 mg, two to three

times per day.

Maximum 6 mg/day.

The total daily dose should be taken as advised by

IMPORTANT: PLEASE READ

your doctor.

Do not change the prescribed dose yourself.

If you

think the effect of your medicine is too weak or too

strong, talk to your doctor.

Do not take TEVA-LORAZEPAM if it is not

prescribed for you.

Your doctor will advise you when to stop taking the

medicine. Your doctor will slowly decrease the

dosage as sudden discontinuation of treatment can

cause the appearance of withdrawal symptoms.

Because elderly patients can be more sensitive to the

effects of TEVA-LORAZEPAM, lower doses may

be prescribed.

TEVA-LORAZEPAM is not for use in children under

18 years of age.

Overdose:

Contact your doctor, regional Poison Control Centre

or pharmacist immediately if you suspect you have

taken an overdose or someone else accidentally takes

your TEVA-LORAZEPAM. If you are unable to

contact them, go to a hospital emergency department

for medical help, even though you may not feel sick.

Show the doctor your bottle of tablets.

In case of drug overdose, contact a health care

practitioner, hospital emergency department or

regional Poison Control Centre immediately, even if

there are no symptoms.

SIDE EFFECTS AND WHAT TO DO

ABOUT THEM

The adverse reaction most frequently reported for

lorazepam was drowsiness. Dizziness, weakness

and unsteadiness were also common.

Release of hostility and other paradoxical effects

such as irritability and excitability, are known to

occur with the use of benzodiazepines. Please tell

your doctor right away if you feel these effects

when taking TEVA-LORAZEPAM. Paradoxical

reactions may be more likely to occur in children or

the elderly. In addition, hypotension (low blood

pressure), mental confusion, slurred speech, over

sedation and abnormal laboratory test results

indicating changes in the liver, kidney and blood

cells have been reported with these drugs.

If you develop symptoms of myasthenia gravis or the

symptoms of your existing myasthenia gravis

worsen, tell your doctor right away. These

symptoms could include muscle weakness that gets

worse with

activity and gets better with rest, drooping

eyelid, blurred or double vision, difficulty

chewing and swallowing, or trouble breathing.

Withdrawal-related side effects:

With sudden discontinuation of treatment with

TEVA-LORAZEPAM symptoms of withdrawal

may occur, including: headache, muscle pain,

convulsions, extreme anxiety, tension, restlessness,

confusion and irritability. In severe cases of

withdrawal, symptoms may include numbness and

tingling of the extremities, hallucinations, increased

sensitivity to light, noise and physical contact and

seizures.

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom/ effect

Talk with

your doctor

or pharmacist

right away

Stop

taking

drug and

seek

immediate

emergency

help

Only

if

severe

In

all

cases

Uncommon

Unusual

behavioural

problems

(aggression,

rage), sudden

anxiety or

excitation;

restlessness,

agitation,

irritability;

hallucinations

(see or hear

things that

are not there)

or delusions;

severe sleep

disturbances,

nightmares,

inappropriate

behavior

Anaphylactic/

anaphylactoid

reactions,

severe

allergic

reactions (red

skin, hives,

itching,

swelling of

the lips, face,

tongue,

throat,

trouble

breathing,

IMPORTANT: PLEASE READ

wheezing,

shortness of

breath, skin

rashes,

blisters of the

skin, sores or

pain in the

mouth or

eyes)

Myasthenia

gravis

(muscle

weakness,

drooping

eyelid, vision

changes,

difficulty

chewing and

swallowing,

trouble

breathing)

Liver

disorder

(symptoms

include

abdominal

pain,

nausea,

vomiting,

yellowing of

skin and

eyes, dark

urine)

Rare

Depression.

Symptoms

may include:

difficulty

sleeping,

changes in

weight,

feelings of

worthlessness,

guilt, regret,

helplessness

hopelessness,

withdrawal

from social

situations,

family

gatherings

and activities

with friends,

reduced

libido (sex

drive), and

thoughts of

death or

suicide.

This is not a complete list of side effects.

For

any unexpected effects while taking TEVA-

LORAZEPAM, contact your doctor or pharmacist.

Reporting Side Effects

You can report any suspected side effects associated

with the use of health products to Health Canada by:

Visiting the Web page on Adverse Reaction

Reporting (https://www.canada.ca/en/health-

canada/services/drugs-health-

products/medeffect-canada/adverse-reaction-

reporting.html) for information on how to

report online, by mail or by fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need

information about how to manage your side effects. The

Canada Vigilance Program does not provide medical

advice.

Bottles: Store at controlled room temperature

(15°C - 30 °C).

Unite Dose (blister): Store between 15°C -25°C.

Keep out of reach and out of sight of children.

MORE INFORMATION

Reminder: This medicine has been prescribed only

for you. Do not give it to anybody else, even if you

think they have the same symptoms that you have, as it

may harm them. If you have any further questions,

please ask your doctor or pharmacist.

This document plus the full Prescribing Information,

prepared for health professionals can be found by

contacting Teva Canada Limited, by:

Phone: 1-800-268-4127 ext. 3;

Email: druginfo@tevacanada.com; or

Fax: 1-416-335-4472

This leaflet was prepared by Teva Canada Limited

Last revised: September 30, 2019

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