Lorazepam 2.5mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Lorazepam 2.5mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains lorazepam 2.5 mg.
Each tablet contains 60 mg of lactose as monohydrate. For full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet
Pink, biconvex, odourless capsule shaped tablets. Scored on one side and engraved MP61.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Adults
Anxiety
Benzodiazepines are only indicated for the short term relief (2 - 4 weeks only) of anxiety that is severe, disabling or subjecting the individual to extreme distress, occurring alone or in association with insomnia or short-term psychosomatic, organic or psychotic illness.
Insomnia
Benzodiazepines are only indicated when the insomnia is severe, disabling or subjecting the individual to extreme distress.
Premedication
Benzodiazepines may be given to sedate and relieve anxiety in apprehensive patients.
Children
Not recommended
4.2 Posology and method of administration
For all indications: treatment should be started with the lowest recommended dose. The maximum dose should not be exceeded. Treatment should be as short as possible (see section 4.4 Special warnings and precautions for use).
In certain cases extension beyond the maximum treatment period may be necessary; if so, it should not take place without re-evaluation of the patient’s status with special expertise.
Adults
Anxiety:
1-4 mg daily in divided doses. Start with a low dose and increase gradually to achieve symptom control.
The patient should be reassessed regularly and the need for continued treatment should be evaluated, especially in the case the patient is symptom free. The overall duration of treatment generally should not be more than 2 - 4 weeks, including a tapering off process.
Insomnia associated with anxiety:
1- 2 mg at bedtime, for administration when required rather than regular use.
Generally the duration of treatment varies from a few days to two weeks with a maximum, including tapering off process of four weeks.
Premedication:
2- 3 mg, preferably to be given the night before surgical or dental procedures. This dosage may be repeated one or two hours before operation and increased, if necessary, to 4 mg.
In the case of dental treatment as opposed to dental surgery 1-2.5 mg one-and-a-half hours to two hours before the treatment.
Special populations
Elderly:
Half the normal adult dose may be sufficient for a therapeutic response in the elderly (see section 4.4 Special warnings and precautions for use).
Patients with impaired liver function:
Use in patients with severe hepatic insufficiency is contraindicated. Patients with mild to moderate impairment may require reduced doses.
Patients with impaired renal function:
Dosage reduction may be required in patients with renal impairment. Children
Not recommended for children.
Method of administration
Oral
4.3 Contraindications
• Respiratory depression
• Myasthenia gravis
• Severe pulmonary insufficiency
• Sleep apnoea syndrome
• Severe hepatic insufficiency
Lorazepam is not appropriate for the treatment of chronic psychosis, phobic or obsessional states and hyperkinesis.
Lorazepam should not be used alone in depression or in anxiety with depression.
Lorazepam should not be given to patients with a known hypersensitivity to the benzodiazepine group of drugs or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Tolerance
Some loss of efficacy to the hypnotic effects of benzodiazepines may develop after repeated use for a few weeks.
Dependence and withdrawal
Use of benzodiazepines may lead to the development of physical and psychic dependence upon these products (see section 4.8 Undesirable effects). The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a history of alcohol or drug abuse, or in patients with personality disorders.
Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headaches, muscle pain, extreme anxiety, tension, restlessness, confusion, and irritability. In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations, epileptic seizures.
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 or sleep disturbances and 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 section 4.2 Posology and method of administration) depending on the indication, and should not exceed 4 weeks including a tapering off process. Extension beyond these periods should not take place without re-evaluation of the situation.
Withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high.
Amnesia
Benzodiazepines may induce anterograde amnesia. The condition occurs most often after several hours after ingesting the product and therefore to reduce the risk, patients should ensure that they will be able to have an uninterrupted sleep of 7-8 hours (see also section 4.8 Undesirable effects).
Psychiatric and paradoxical reactions
Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. Should this occur, use of the medicinal product should be discontinued. They are more likely to occur in children and the elderly.
In cases of bereavement, psychological adjustment may be inhibited by lorazepam.
Specific patient groups
Benzodiazepines should not be given to children without careful assessment of the need to do so; the duration of treatment must be kept to a minimum. The elderly should be given a reduced dose (see section 4.2 Posology and method of administration). A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression.
Hepatic impairment: Benzodiazepines are contra-indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy; patients with mild to moderate impairment may require reduced doses.
Renal impairment: Caution is required when treating patients with renal impairment and doses may need to be reduced.
Benzodiazepines are not recommended for the primary treatment of psychotic illness.
Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients).
Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.
Excipient with known effect
Lorazepam tablets contain 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
The metabolism of most benzodiazepines is mediated mainly by the cytochrome P450 system. Compounds, which inhibit certain enzymes (particularly cytochrome P450), may enhance the activity of benzodiazepines. To a lesser degree this also applies to benzodiazepines that are metabolised only by glucuronide conjugation, such as lorazepam.
Enhanced sedation or respiratory and cardiovascular depression may occur if benzodiazepines are given with other drugs that have CNS-depressant properties. This can increase drowsiness and reduce alertness, which increases the risk of accidents when driving or handling other potentially dangerous machinery, and may make the performance of everyday tasks more difficult and hazardous.
Hypnotics and anxiolytics: The concurrent use of two or more drugs that are CNS depressants can increase drowsiness and reduce alertness.
The sedative effect of lorazepam may be enhanced when the product is used in combination with alcohol (even in small amounts). This affects the ability to drive or use machines (see section 4.7 Effects on ability to drive and use machines). Alcohol has been reported to increase aggression or amnesia and/or reduce the anxiolytic effects of some benzodiazepines.
Additive CNS depressant effects are predicted when sodium oxybate is given with other CNS depressant drugs such as lorazepam, and concurrent use of sedative hypnotics should be avoided.
Antipsychotics: Marked sedation, severe hypotension, respiratory depression, loss of consciousness, hypersalivation, ataxia and symptoms of delirium have been reported on concomitant use of lorazepam with clozapine. Concurrent use should be very well monitored for any evidence of CNS depression because of severity of the reaction.
Valproate reduces the glucuronidation of lorazepam, thereby decreasing its clearance and increasing its effects. It is advised that the dose of lorazepam should be reduced in patients taking valproate.
Antidepressants: The concurrent use of tricyclic antidepressants and benzodiazepines is not uncommon and normally appears to be uneventful. However, concurrent use has led to adverse effects (e.g. drowsiness, incoordination). Benzodiazepines may increase the risks of carrying out complex tasks (e.g. driving) if taken together with tricyclic antidepressants.
There is limited evidence to support the sedation could be increased by the concurrent use of any SSRI and benzodiazepines.
Mirtazapine has prominent sedative effects and these are likely to be additive with those of benzodiazepines.
Sedative Antihistamines: Benzodiazepines impair psychomotor performance, and an enhanced sedative effect would be expected if known sedative antihistamines are given with benzodiazepines.
Anaesthetics: Benzodiazepines may potentiate the effects of general anaesthetics. In general, this may reduce the dose of anaesthetic required and/or slow recovery from the anaesthetic. In many cases this interaction is exploited clinically.
Both benzodiazepines and local anaesthetics are CNS depressants and therefore their concurrent use may result in additive CNS depression. Consideration should be given to the potential for increased sedation.
Analgesics: The concurrent use of opioids and benzodiazepines results in both beneficial analgesic effects, and enhanced sedation and respiratory depression; however, in some cases benzodiazepines have antagonised the respiratory depressant effects of opioids, and, rarely, have antagonised their analgesic effects.
In the case of narcotic analgesics, enhancement of the euphoria may also occur leading to an increase in psychic dependence.
Antiepileptics: Carbamazepine, phenobarbital, and phenytoin are all inducers of hepatic drug-metabolising enzymes. Therefore, in patients receiving longterm therapy with these drugs the metabolism of benzodiazepines may be enhanced. However, use of valproate semisodium with lorazepam has resulted in raised concentrations of lorazepam due to inhibition of glucuronidation of lorazepam.
Antihypertensives: Enhanced hypotensive effect occur when Lorazepam is combined with ACE-inhibitors, alpha-blockers, angiotensin-II receptor antagonists, calcium channel blockers, adrenergic neurone blockers, beta-blockers, centrally acting antihypertensive agents (e.g. clonidine, methyldopa, moxonidine), nitrates, vasodilators (e.g. hydralazine, minoxidil, sodium nitroprusside) and diuretics.
Antivirals: Interactions between the HIV-protease inhibitors and the benzodiazepines that are metabolised mainly by glucuronidation, such as lorazepam, are less likely to occur than those metabolised by CYP3A4. However, some HIV-protease inhibitors, such as ritonavir, also induce glucuronidation, and so in theory they could induce the metabolism of these benzodiazepines decreasing their effects.
Hormonal contraceptives: The pharmacokinetic interactions between the combined hormonal contraceptives and the benzodiazepines are established interactions, but of uncertain clinical importance. Those taking benzodiazepines that are metabolised to glucuronides (such as lorazepam) might need a dose increase, but this is not proven.
Bronchodilators: Aminophylline and theophylline appear to antagonise the effects of the benzodiazepines (mainly sedative effects, but possibly also anxiolytic effects).
Probenecid: Probenecid inhibits the renal tubular clearance of many drugs and their metabolites, including some of the benzodiazepines. It also inhibits the glucuronidation of nitrazepam and lorazepam by the liver. The overall result is that these benzodiazepines accumulate and their effects are increased. Patients should be alert for increases in the effects (sedation, anterograde amnesia) of lorazepam and the dose should be reduced as necessary.
Other relevant interactions
Caffeine: Caffeine appears to antagonise the effects of benzodiazepines, (mainly sedative effects, but possibly also anxiolytic effects), particularly at high doses.
4.6 Fertility, Pregnancy and lactation
Pregnancy
If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance 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 at high doses, 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.
Breast-feeding
Although the effects of lorazepam on breast-fed infants is unknown, its use by mothers during breast-feeding might be of concern since benzodiazepines are found in breast milk, and thus could conceivably alter the CNS function in the infant both in the short and long-term. Benzodiazepines should, therefore, not be given to breast feeding mothers.
4.7 Effects on ability to drive and use machines
This medicine can impair cognitive function and can affect a patient’s ability to drive or to use machines 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
If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased (see also section 4.5 Interactions).
4.8 Undesirable effects
Drowsiness, sedation, muscle weakness, and ataxia are the most frequent adverse effects of lorazepam use. These phenomena occur predominantly at the start of therapy and usually disappear with repeated administration.
Less frequent effects include vertigo, headache, confusion, depression (see below), slurred speech or dysarthria, gastrointestinal disturbances, changes in libido, tremor, visual disturbances, urinary retention or incontinence, changes in salivation, and amnesia (see below).
Jaundice, blood disorders and hypersensitivity reactions have been reported rarely; raised liver enzyme values have occurred. Respiratory depression and hypotension occasionally occur with high dosage.
Amnesia
Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnesiac effects may be associated with inappropriate behaviour (see section 4.4 Special warnings and precautions for use).
Depression
Pre-existing depression may be unmasked during benzodiazepine use. Psychiatric and paradoxical reactions
Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines or benzodiazepine-like agents. They may be quite severe with this product. They are more likely to occur in children and the elderly.
Dependence and withdrawal
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 section 4.4 Special warnings and precautions for use). Psychic dependence may occur. Abuse of benzodiazepines has been reported.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme [www.mhra.gov.uk/yellowcard].
4.9 Overdose
As with other benzodiazepines, overdose should not present a threat to life unless combined with other CNS depressants (including alcohol). The treatment of benzodiazepine overdosage is generally symptomatic and supportive. Patients who are asymptomatic after 4 hours are unlikely to develop severe toxicity.
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.
Management
In the management of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken.
The benefit of gastric decontamination is unclear. Consider activated charcoal in adults or children who have taken more than a potentially toxic amount within 1 hour, provided the airway can be protected. Special attention should be paid to respiratory and cardiovascular functions in intensive care.
The specific benzodiazepine antagonist, flumazenil, is rarely required, and can be hazardous, particularly in mixed overdoses involving tricyclic antidepressants or in benzodiazepine-dependent patients; the UK Poisons Information Service, contra-indicates its use in mixed overdoses. However, use of flumazenil may sometimes provide an alternative to ventilation, particularly in patients with severe respiratory disorders, or in children who are naive to benzodiazepines.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anxiolytic - Benzodiazepine derivative ATC Code: N05BA06
Lorazepam is effective in alleviating the symptoms of pathological anxiety in anxiety states, and in anxiety associated with other psychiatric disorders. In general it should not be used in non-pathological anxiety where it may inhibit rather than enhance psychological adjustment. In the case of mixed depression and anxiety the therapeutic effect is on the anxiety symptoms only. Lorazepam is an agonist at benzodiazepine receptors in the central nervous system (CNS). The CNS depression produced by lorazepam is dose-related. An oral dose of 5 mg produces obvious sedation and, in addition, an oral dose of 5 mg produces anterograde amnesia. Lorazepam produces dose-related impairment of psychomotor function e.g. critical flicker fusion frequency and reaction time. Lorazepam produces no significant change in blood pressure, pulse rate, ECG or cardiac output.
5.2 Pharmacokinetic properties
Absorption
Following oral administration lorazepam is absorbed from the gastro-intestinal tract. Peak plasma level is reached after approximately 2 hours and oral bioavailability of lorazepam averages 90%. The mean half-life of lorazepam elimination in humans is 15 hours with the usual range of 8 to 25 hours in healthy individuals.
The half-life is not impaired by the ageing process or renal disease, but may be prolonged in the case of hepatic dysfunction.
Distribution
The volume of distribution is 1-2 L/kg. The plasma protein binding is 88 to 92%. It crosses the blood-brain barrier and the placenta; it is also distributed into breast milk.
Biotransformation
The major metabolic pathway of lorazepam in humans involves conjugation at the III position with glucoronic acid in the liver. This yields a water-soluble metabolite, which is pharmacologically inactive.
Elimination
Up to 75% of the dose is eliminated mainly by renal excretion as metabolite within 5 days. The other metabolites of lorazepam are hydroxylorazepam, quinazoline, carboxylic acid derivatives; these metabolites are not responsible for the pharmacological effect to any significant degree.
Preclinical safety data
5.3
No relevant information additional to that contained elsewhere in the SmPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline cellulose Lactose monohydrate Talc
Sodium starch glycollate Magnesium stearate Erythrosine aluminium lake E127
6.2 Incompatibilities
Not applicable
6.3 Shelf life
Containers: 36 months Blister packs: 24 months
6.4 Special precautions for storage
Containers: Do not store above 25°C. Keep the container tightly closed. Blister packs: Do not store above 25°C. Store in the original package.
6.5 Nature and contents of container
High density polystyrene with polythene lids and/or polypropylene containers with polypropylene or polythene lids and polyurethane or polythene inserts.
Packs of 14, 15, 21, 28, 30, 50, 56, 60, 84, 100, 250, 500 and 1000 tablets
PVC/Aluminium foil blister strips composed of 250 micron PVC glass-clear/bluish rigid PVC (pharmaceutical grade), and 20 micron hard tempered aluminium foil, coated on the dull side with 6-7 gsm heat-seal lacquer and printed on the bright side.
Packs of 14, 15, 21, 28, 30, 50, 56, 60, 84, 100, 250, 500 and 1000 tablets
6.6 Special precautions for disposal
Not Applicable
7 MARKETING AUTHORISATION HOLDER
Genethics Europe Limited 41 - 43 Klimentos Klimentos Tower Nicosia 1061 Cyprus
8 MARKETING AUTHORISATION NUMBER(S)
PL 42976/0035
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
13/03/2009
10 DATE OF REVISION OF THE TEXT
22/07/2016