INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
ATIVAN® 0,5 mg TABLETS
ATIVAN® 1 mg TABLETS
ATIVAN® 2,5 mg TABLETS

SCHEDULING STATUS:
S5

PROPRIETARY NAME
(and dosage form):

ATIVAN^® 0,5 mg TABLETS
ATIVAN^® 1 mg TABLETS
ATIVAN^® 2,5 mg TABLETS

COMPOSITION:
ATIVAN 0,5 mg tablet contains 0,5 mg lorazepam
ATIVAN 1 mg tablet contains 1 mg lorazepam
ATIVAN 2,5 mg tablet contains 2,5 mg lorazepam
Chemically, Lorazepam is known as:
7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepine-2-one.
ATIVAN 2,5 mg tablets contain TARTRAZINE.

PHARMACOLOGICAL CLASSIFICATION:
A 2.6 Tranquillisers.

PHARMACOLOGICAL ACTION:
ATIVAN is a benzodiazepine. It has anxiolytic, sedative and hypnotic properties. The exact mechanism of action of benzodiazepines has not yet been elucidated; however benzodiazepines appear to work through several mechanisms. Benzodiazepines presumably exert their effects by binding to specific receptors at several sites within the central nervous system, thereby potentiating the effects of synaptic or presynaptic inhibition mediated by gamma-aminobutyric acid or directly affecting the action potential generating mechanisms.
Pharmacokinetics
ATIVAN (lorazepam) tablets are well absorbed when given orally. Peak concentrations in plasma occur approximately 2 hours following administration. The elimination half-life of unconjugated lorazepam in human plasma is approximately 12-16 hours. At clinically relevant concentrations, lorazepam is approximately 90% bound to plasma proteins. The plasma levels of lorazepam are proportional to the dose given.
Excessive medicine accumulation has not been observed following multi-dose therapy in young healthy subjects. Conjugation with glucuronic acid to form the inactive glucuronide is the major metabolic pathway of lorazepam. It has no active metabolites. Seventy to seventy five percent of the dose is excreted as the glucuronide in the urine. Lorazepam is not hydroxylated to any significant extent, nor is it a substrate for N-dealkylating enzymes of the cytochrome P450 system.
Haemodialysis did not have any significant effect on the pharmacokinetics of intact lorazepam, but substantially removed the inactive glucoronide from the plasma.

INDICATIONS:
ATIVAN is indicated for the following:
Management of anxiety disorders or for the short-term relief of the symptoms of anxiety or anxiety associated with depressive symptoms.
ATIVAN is indicated only when the disorder has not responded to non-drug therapy, and is severe, disabling, or subjecting the individual to unacceptable distress. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.
Patients with renal function impairment or low serum albumin should receive decreased initial dosage since elimination may be decreased in these patients.

CONTRA-INDICATIONS:
Known sensitivity, or a history of hypersensitivity to benzodiazepines, including ATIVAN tablets or its components and in patients with pre-existing CNS depression or coma. Safety in pregnancy has not been established.
ATIVAN is contra-indicated in patients with:
1.        Sleep apnoea syndrome.
2.        Respiratory insufficiency.

WARNINGS:
Patients should be warned not to operate dangerous machinery or motor vehicles until it is known that they do not become drowsy or dizzy from ATIVAN. Patients should be advised that since their tolerance for alcohol and other central nervous system depressants will be diminished in the presence of ATIVAN, these substances should either be avoided or taken in reduced dosage.
ATIVAN is not intended for the primary treatment of psychotic illness or depressive disorders, and should not be used alone to treat depressed patients. The use of benzodiazepines may have a disinhibiting effect and may release suicidal tendencies in depressed patients. The need for continued therapy with ATIVAN should be determined periodically. Benzodiazepine therapy should be discontinued gradually.
ATIVAN 2,5 mg tablets contain FD&C Yellow No 5 (Tartrazine), which may cause allergic type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of tartrazine-sensitivity in the general population is currently thought to be low, it is frequently seen in patients who have aspirin-sensitivity.

DOSAGE AND DIRECTIONS FOR USE:
Anxiety and tension associated with everyday life does not require treatment with an anxiolytic.
It is recommended that the need for continued therapy with lorazepam be determined periodically.
Dosage for children under 12 years has not been established.
Dosage and duration of therapy should be individualised. The lowest effective dose should be prescribed for the shortest time possible. The maximum dose should not be exceeded. Generally, the duration of treatment should not exceed 8 to 12 weeks, including tapering. Extension of the treatment period should not take place without re-evaluation of the need for continued therapy especially in cases where the patient is symptom-free. Treatment should be discontinued gradually.
The average daily dosage for treatment of anxiety is 2 mg to 3 mg administered in two to four portions; however, the daily dose may range between 1 mg and 6 mg, a maximum of 10 mg has been used. The largest dose should be taken before bedtime.
Elderly or debilitated patients, or patients with impaired renal or hepatic function generally require lower or less frequent doses. These patients should be monitored frequently, and dosages should be adjusted carefully according to patient response. For elderly or debilitated patients, an initial dosage of 1 or 2 mg per day in divided doses is recommended, to be adjusted as needed and tolerated.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects:
Adverse reactions, when they occur, are usually observed at the beginning of therapy and generally decrease in severity or disappear with continued use, or upon decreasing the dose.
Most frequently reported adverse reactions include the following:

daytime drowsiness, sedation, dizziness, muscle weakness and ataxia.

Less frequently reported adverse reactions associated with benzodiazepines including lorazepam include the following:

vertigo, headache, confusion, mental depression, fatigue, slurred speech or dysarthria, changes in libido, tremor, visual disturbances, reduced alertness, numbed emotions, nausea, appetite changes, sleep disturbance, dermatological reactions, gastro-intestinal symptoms, urinary retention or incontinence, changes in salivation and amnesia.

Some patients may experience a paradoxical excitation which may lead to hostility, aggression and disinhibition. Respiratory depression and hypotension occasionally occur with high dosage. Rebound anxiety and insomnia may be the result of tolerance to the effects of lorazepam or part of a withdrawal syndrome.
Rarely reported adverse reactions include the following:

blood dyscrasias, jaundice, abnormal liver function tests or memory impairment and hypersensitivity reactions.

Transient anterograde amnesia or memory impairment has been reported in association with the use of benzodiazepines.
Drug abuse and dependence:
The use of benzodiazepines may lead to physical and psychological dependence. When used at appropriate doses for short-term treatment of anxiety, the dependence potential is low. 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 disorder. Therefore use in persons who are drug addicts or alcoholics should be avoided.
If physical dependence develops, abrupt termination of treatment may be accompanied by withdrawal symptoms. Symptoms reported following discontinuation of benzodiazepines include headaches, muscle pain, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating and the occurrence of rebound phenomena whereby the symptoms that led to the treatment with benzodiazepines recur in an enhanced form. These symptoms may be difficult to distinguish from the original symptoms for which the medicine was prescribed.
In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, tinnitus, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, involuntary movements, vomiting, hallucination, and convulsions.
Convulsions may be more common in patients with pre-existing seizure disorders or who are taking other medicines that lower the convulsive threshold such as antidepressants.
Withdrawal symptoms, especially the more serious ones, are more common in those patients who have received high doses over an extended period of time. However, withdrawal symptoms have also been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels, especially when discontinuation is abrupt. Since the risk of withdrawal/rebound phenomena is greater after abrupt discontinuation, the medicine should be discontinued gradually.
Special precautions:
ATIVAN should be used with extreme caution in patients with a history of alcohol or drug abuse.
Anxiety may be a symptom of several other disorders. The possibility should be considered that the complaint may be related to an underlying physical or psychiatric disorder for which there is more specific treatment.
In patients where gastro-intestinal or cardiovascular disorders coexist with anxiety, it should be noted that ATIVAN has not been shown to be of significant benefit in treating the gastro-intestinal or cardiovascular component.
Pre-existing depression may emerge during benzodiazepines use (see 'Warnings').
Caution should be used in the treatment of patients with acute narrow-angle glaucoma or myasthenia gravis.
Patients with impaired renal or hepatic functions should be monitored frequently and have their dosage adjusted carefully to patient response. Lower doses are indicated in these patients. The same precautions apply to elderly or debilitated patients and patients with severe respiratory insufficiency.
The use of benzodiazepines may precipitate encephalopathy in patients with severe hepatic insufficiency.
Some patients taking benzodiazepines have developed blood dyscrasia, and some have had elevations in liver enzymes. Periodic haematologic and liver-function assessments are recommended when long-term therapy is clinically necessary.
Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rage, nightmares, hallucinations, psychoses, and inappropriate behaviour have been occasionally reported during benzodiazepine use. Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the medicine should be discontinued.
Although hypotension has occurred infrequently, benzodiazepines should be administered with caution to patients in whom a drop in blood pressure might lead to cardiovascular or cerebrovascular complications. This is particularly important in elderly patients.
In patients with anxiety accompanying depression, the possibility of attempted suicide should be borne in mind, and large quantities of ATIVAN should not be prescribed.
Oesophageal dilatation occurred in rats treated with lorazepam for more than one year at 6 mg/kg per day. The no-effect dose was 1,25 mg/kg per day (approximately 6 times the maximum human therapeutic dose of 10 mg per day). The effect was reversible only when the treatment was withdrawn within two months of first observation of the phenomenon.
The clinical significance of this is unknown. However, use of lorazepam for prolonged periods and in geriatric patients requires caution, and there should be frequent monitoring for symptoms of upper GI disease.
Duration:
The duration of treatment should be as short as possible (see dosage). Extension beyond these periods should not take place without revaluation of the situation. It is important that the patients should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms, should they occur while the product is being discontinued.
Use during pregnancy:
Benzodiazepines should not be used during pregnancy. If the medicine is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance of the drug if she intends to become or suspects that she is pregnant.
Benzodiazepines may cause foetal damage when administered to pregnant women. An increased risk of congenital malformations associated with the use of anxiolytic agents such as chlordiazepoxide, diazepam, and meprobamate has been suggested in several studies.
In humans, umbilical cord blood samples indicate placental transfer of benzodiazepines for several weeks or more preceding delivery and have been reported to have withdrawal symptoms during the postnatal period. Symptoms such as hypoactivity, hypotonia, hypothermia, respiratory depression, apnoea, 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.
Neonates appear to conjugate lorazepam slowly, the glucuronide being detectable in the urine for more than seven days. Glucuronidation of lorazepam may competitively inhibit the conjugation of bilirubin, leading to hyperbilirubinaemia in the newborn.
ATIVAN tablets are not recommended for obstetrical use.
Use during lactation:
There is evidence that lorazepam is excreted in pharmacologically insignificant amounts in human breast milk. ATIVAN should not be administered to nursing women.
Paediatric use:
The safety and effectiveness of ATIVAN in children has not been established and such use is not recommended.
Drug Interactions:
The benzodiazepines, including ATIVAN, produce additive CNS depressant effects when co-administered with other CNS depressants, e.g., alcohol, barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anaesthetics.
There have been reports of marked sedation, excessive salivation, and ataxia when lorazepam and clozapine were given concomitantly.
There have been reports of excessive stupor, significant reduction in respiratory rate, and, in one patient, hypotension when lorazepam and loxapine were given concomitantly.
Laboratory test interactions:
No interference with laboratory tests has been identified or reported with the use of ATIVAN.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
In the management of overdosage, it should be borne in mind that multiple agents may have been taken.
Symptoms:
Overdosage of benzodiazepines is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion, and lethargy. In more serious cases, and especially when other CNS-depressant agents or alcohol were ingested, symptoms may include ataxia, hypotension, hypotonia, respiratory depression, stage one (1) to three (3) coma, and very rarely, death.
Management:
If ingestion was recent, induced vomiting and/or gastric lavage should be undertaken when appropriate, followed by general supportive care, monitoring of vital signs, and close observation of the patient. If there is no advantage in emptying the stomach, activated charcoal may be effective in reducing absorption. Hypotension, though unlikely, may be controlled with noradrenaline. Lorazepam is poorly dialyzable.
The benzodiazepine antagonist flumazenil may be useful in hospitalised patients for the management of benzodiazepine overdosage. Flumazenil product information should be consulted prior to use.

IDENTIFICATION:
ATIVAN 0,5 mg tablet is white, round, and 5 mm in diameter.
ATIVAN 1 mg tablet is white, round, flat, 6,5 mm in diameter, scored on the one side and with "1,0" imprinted on the other side.
ATIVAN 2,5 mg tablet is yellow, round, flat, 7,94 mm in diameter, scored on the one side and with "2,5" imprinted on the other side.

PRESENTATION:
ATIVAN 0,5 mg, 1 mg and 2,5 mg tablets are blister packed in cartons of 60 and 100 tablets each.

STORAGE DIRECTIONS:
Store in a cool (below 25°C), dry place.
Keep out of reach of children.

REGISTRATION NUMBERS:

ATIVAN 0,5 mg:	X/2.6/82
ATIVAN 1 mg:	D/2.6/126
ATIVAN 2,5 mg:	D/2.6/128

NAME AND BUSINESS ADDRESS OF APPLICANT:
AKROMED PRODUCTS (PTY) LIMITED
Building 12
Healthcare Park
Woodlands Drive
Woodmead
Sandton        2148

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
7th November 1989

Trademark and product under licence of WYETH-AYERST LABORATORIES, U.S.A.

308458        030417
Harry's Printers-K00000 D03

Updated on this site: January 2005
Source: Pharmaceutical Industry
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