Lorazepam Tablets Bp 2.5 Mg

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Lorazepam Tablets BP 2.5 mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Lorazepam BP 2.5 mg

3 PHARMACEUTICAL FORM

Tablets for oral administration.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

The short-term (2 - 4 weeks) treatment of severe anxiety occurring alone or in association with insomnia or psychosomatic, organic or psychotic illness.

4.2 Posology and method of administration

Adults:

All indications 1-4mg daily in divided doses, with the lowest effective dose being used. Treatment should be started with the lowest recommended dose. The maximum dose should not be exceeded.

Lorazepam should not be used for long term chronic use;

Routine repeat prescriptions should be avoided;

Treatment in all patients should be withdrawn gradually with careful monitoring and assessment to minimise possible withdrawal symptoms.

Children:

Not recommended for use in children.

Elderly:

At least half the normal adult dose may be effective.

Renal or Hepatic Impairment:

Lower doses may be sufficient in these patients.

Route of Administration: Oral

4.3 Contraindications

Should not be given to patients

• with a previous history of sensitivity to benzodiazepines, including Lorazepam tablets and any of its ingredients.

• myasthenia gravis;

• acute pulmonary insufficiency;

• sleep apnoea syndrome;

• severe hepatic impairment

4.4 Special warnings and precautions for use

Lorazepam should not be used for long term chronic use as this may result in the development of tolerance and dependence.

Anaphylactic reactions

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 dyspnoea, 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.

Dependence

Doctors should be aware that repeated doses of Lorazepam over a prolonged period of time may lead to physical and psychological dependence. The risk of dependence on Lorazepam is low when used at the recommended dose and duration, but increases with higher doses and longer term use. The risk of dependence is further increased in patients with a history of alcoholism or drug abuse or in patients with significant personality disorders. Therefore, use in individuals with a history of alcoholism or drug abuse should be avoided.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headache, muscle pain, extreme anxiety, tension, depression, insomnia, restlessness, confusion, sweating,irritability. and the occurrence of ‘rebound phenomena whereby the symptoms that led to treatment with benzodiazepines recur in an enhanced form. These symptoms may be difficult to distinguish from the original symptoms for which the drug was prescribed.

In severe cases, the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, involuntary movements, vomiting, hallucinations or epileptic seizures (convulsions). Seizures may be common in patients with pr-existing seizure disorders or who are taking other drugs that lower the convulsive threshold, such as antidepressants.

Rebound Insomnia and Anxiety:

A transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety, sleep disturbances or restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.

Duration of Treatment

The duration of treatment should be as short as possible. (See indications). It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage will be progressively decreased. Moreover it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur while the medicinal product is being discontinued.

There are indications that, in the case of benzodiazepines with a short duration of action, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high.

Psychiatric and ‘Paradoxical’ Reactions

Benzodiazopines including lorazepam are not intended for the primary treatment of psychotic illness or depressive disorders and should not be used alone to treat depression or anxiety associated with depression. The use of benzodiazepines may have a disinhibiting effect and may release suicidal tendencies in depressed patients.

Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse effects are known to occur when using benzodiazepines. They are more likely to occur in children and the elderly. Should this occur, use of the drug should be discontinued.

Transient anterograde amnesia or memory impairment has been reported in association with the use of benzodiazepines. This effect may be advantageous when Lorazepam is used as a premedicant.

Specific patient groups Chronic respiratory insufficiency

A lower dose is recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression.

Renal and hepatic impairment

Patients with impaired renal or hepatic function should be monitored frequently and have their dosage adjusted carefully according to patient response. Lower doses may be sufficient in these patients. The use of benzodiazepines may worsen hepatic encephalopathy.

Some patients taking benzodiazepines have developed a blood dyscrasia and some have had elevations in liver enzymes. Periodic haematologic and liver-function assessments are recommended where repeated courses of treatment are considered clinically necessary.

As with all CNS-depressants, the use of benzodiazepines may precipitate encephalopathy in patients with severe hepatic insufficiency. Therefore, use in these patients is contraindicated.

Hypotension

Although hypotension has occurred only rarely, 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. Dosage reduction is thus recommended in elderly patients and those suffering from cerebral vascular changes.

Glaucoma

Caution should be used in the treatment of patients with acute narrow-angle glaucoma.

Alcohol and drug abuse

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.

Psychiatric disorders

Anxiety or insomnia 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.

Excipients:

This product contains the excipient, lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Not recommended: Concomitant intake with alcohol.

The sedative effect may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines.

Take into account: Combination with CNS depressants Enhancement of the central depressive effect may occur in cases of concomitant use with barbiturates, antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anti-epileptic (convulsants) drugs, anaesthetics and sedative antihistamines.

Concurrent administration of lorazepam with sodium valproate may result in reduced clearance (20% - 40%) and increased plasma concentrations of lorazepam. Therefore clinical monitoring is advised and lorazepam dosage should be reduced when appropriate.

Concurrent administration of lorazepam with probenecid may result in reduced clearance, increased elimination half-life and increased concentrations of lorazepam. Clinical monitoring is recommended and the lorazepam dosage should be reduced when appropriate.

In the case of narcotic analgesics enhancement of the euphoria may also occur leading to an increase in psychic dependence.

Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines. To a lesser degree this also applies to benzodiazepines that are metabolised only by conjugation. Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation and ataxia.

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

4.6 Pregnancy and lactation

Lorazepam should not be used during pregnancy, especially during the first and last trimesters, unless in the judgement of the physician such administration is clinically justifiable. Benzodiazepines may cause foetal damage when administered to pregnant women.

If lorazepam is prescribed to a woman of child bearing potential, she should be warned to contact her physician regarding discontinuation of the product if she intends to become or suspects that she is pregnant.

If, for compelling medical reasons, the product is administered during the late phase of pregnancy or during labour, effects on the neonate, such as hypothermia, hypotonia and moderate respiratory depression, can be expected, due to the pharmacological action of the compound.

Moreover, infants born to mothers who took benzodiazepines chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.

Symptoms such as 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.

Since benzodiazepines transfer to breast milk, lorazepam should not be given to breast feeding mothers unless the expected benefit to the woman outweighs the potential risk to the infant.

4.7 Effects on ability to drive and use machines

Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the ability to drive or to use machines. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased. (See also Interactions). Patients that are affected should be advised to avoid driving or operating machinery.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

The medicine is likely to affect your ability to drive,

• Do not drive until you know how the medicine affects you

• It is an offence to drive while under the influence of this medicine

However, you would not be committing an offence (called ‘statutory defence’) if:

• The medicine has been prescribed to treat a medical or dental problem and

• You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

• It was not affecting your ability to drive safely.

4.8 Undesirable effects

Adverse reactions are listed in the table in CIOMS frequency categories:

Very common: Common: Uncommon: Rare:

Very rare:

> 10%

> 1% and < 10%

> 0.1% and < 1%

> 0.01% and < 0.1% < 0.01%

Undetermined: Insufficient data to calculate significant frequencies.

System Organ Class and Frequency

Very

common ^ 10%)

Common ^ 1 % and < 10%)

Uncommon ^ 0.1% and < 1%)

Undetermined

Blood and lymphatic system

Thrombocytopenia,

agranulocytosis,

pancytopenia

System Organ Class and Frequency	Very common ^ 10%)	Common ^ 1 % and < 10%)	Uncommon ^ 0.1% and < 1%)	Undetermined
disorders
Immune system disorders				Hypersensitivity reactions, anaphylactic reactions, angioedema.
Endocrine disorders				Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
Metabolism & nutrition disorders				Hyponatraemia
Psychiatric disorders		Confusion, depression, unmasking of depression.		Disinhibition, euphoria, suicidal ideation/attempt, Paradoxical reactions², including anxiety, agitation, excitation, hostility, aggression, rage, sleep disturbances/insomnia, sexual arousal and hallucinations.
Nervous system disorders*	Sedation, drowsiness,	Ataxia, dizziness		Extrapyramidal symptoms, tremor, vertigo, visual disturbances (including diplopia and blurred vision), dysarthria/slurred speech, headache, convulsions/seizures, amnesia¹, coma
Vascular disorders				Hypotension
Respiratory, thoracic and mediastinal disorders+				Respiratory depression, apnoea, worsening of sleep, worsening of obstructive pulmonary disease
Gastrointestinal disorders			Nausea,	Constipation
Hepatobiliary disorders				Increase in bilirubin, increase in liver transaminases, increase in alkaline phosphatase
Skin and subcutaneous tissue disorders				Allergic skin reactions, alopecia
Reproductive system and breast disorders			Change in libido, impotence,

System Organ Class and Frequency

Very

common ^ 10%)

Common ^ 1 % and < 10%)

Uncommon ^ 0.1% and < 1%)

Undetermined

decreased

orgasm

General

disorders

Fatigue

Muscle

weakness,

asthenia

Hypothermia

* Benzodiazepine effects on the CNS are dose dependent, with more severe CNS depression occurring with higher doses.

+ The extent of respiratory depression with benzodiazepines is dose dependent with more severe depression occurring with high doses.

¹ Transient anterograde amnesia or memory impairment may occur using therapeutic doses, the risk increasing at higher doses (see section 4.4).

Amnesic effects may be associated with inappropriate behaviour.

Paradoxical reactions are more likely to occur in children and the elderly (see section 4.4).

Dependence

Use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena. (See warnings and precautions).

Abuse of benzodiazepines has been reported.

4.9 Overdose

As with other benzodiazepines, overdose should not present a threat to life unless combined with other CNS depressants (including alcohol).

Symptoms

Overdose 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, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death.

Treatment

In the management of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken.

Following overdose with oral benzodiazepines, vomiting should be induced (within one hour) if the patient is conscious or gastric lavage undertaken with the airway protected if the patient is unconscious. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption.

Special attention should be paid to respiratory and cardiovascular functions in intensive care. This will be mainly supportive including monitoring of

vital signs and close observation of the patient. A clear/adequate airway should be maintained (including during sleep) and assisted respiration used as needed. Hypotension, though unlikely, may be controlled with noradrenaline. Lorazepam is poorly dialysable.

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. The physician should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in tricyclic antidepressant overdose..

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anxiolytic benzodiazepine derivatives;

ATC code: N05BA06

Lorazepam is a short-acting benzodiazepine anxiolytic with sedative, muscle relaxant and amnesic properties.

5.2 Pharmacokinetic properties

Lorazepam is rapidly absorbed from the gastro intestinal tract and is metabolised by a simple one-step process to a pharmacologically inactive glucuronide. The elimination half-life is about 12 hours so that steady state plasma levels are quickly reached, and there is minimal risk of excessive accumulation, giving a wide margin of safety.

5.3 Preclinical safety data

Not applicable

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose powder BP,

Maize starch BP,

Povidone BP,

Water BP,

Sodium starch glycollate (primojel) BP, Colloidal silicon dioxide (aerosil 200) USP, Magnesium stearate BP,

Anstead dispersed orange No. 11348 (E110)

6.2 Incompatibilities

No major incompatibilities other than those reported under 4.5 above.

6.3 Shelf life

36 months

6.4 Special precautions for storage

Store in a cool, dry place and protect from light

6.5 Nature and contents of container

Polypropylene tubular container with an open end equipped to accept a polyethylene closure with a tamper-evident tear strip containing, 7, 14, 21, 28, 30, 56, 60, 84, 90, 100, 112, 120, 250, 500 and 1000 tablets.

6.6 Special precautions for disposal

No special instructions.

7 MARKETING AUTHORISATION HOLDER

Norton Healthcare Ltd.,

T/A IVAX Pharmaceuticals Albert Basin,

Royal Docks,

London, E16 2QJ.

MARKETING AUTHORISATION NUMBER(S)

PL 00530/0081

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/04/1981 / 24/02/2009

DATE OF REVISION OF THE TEXT

23/09/2014