Lorazepam 2.5 Mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Lorazepam 2.5 mg tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains lorazepam 2.5 mg.
Excipient:
2.5 mg: lactose monohydrate 172.05 mg per tablet.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet
Lorazepam 2.5 mg: white, round, flat, bevelled, scored, tablets, diameter between 9.0 mm - 9.2 mm, thickness between 3.3 mm - 3.5 mm, and a theoretical weight of 266.3 mg.
The tablet can be divided into equal halves.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Lorazepam is indicated for:
-Short-term symptomatic treatment of anxiety and insomnia caused by anxiety, where the anxiety is severe, disabling or subjecting the individual to extreme distress.
-Premedication before general anaesthesia or before minor surgical procedures, investigations or operative dentistry.
4.2 Posology and method of administration
General:
For oral administration.
The dosage and duration of therapy should be individualised. The lowest effective dose should be prescribed for the shortest time possible. Since the risk of withdrawal and rebound phenomena is greater after abrupt withdrawal, the drug should be discontinued gradually for all patients (see section 4.4).
The maximum daily dose of 4mg should not be exceeded.
In general the duration of treatment varies from a few days to 4 weeks, including the tapering off process.
Extension of the treatment period should not take place without re-evaluation of the need for continued therapy.
If the daily dose is taken as single dose in the evening it should not be taken on a full stomach. Due to a delayed onset of effect and depending on the length of the sleeping period a hang-over effect might be possible during the following day (see Section 4.4).
Adults:
Anxiety: Initial dose 0.5 mg, 2-3 times a day, maintenance dose is up to 2.5mg per day. The daily dose can be divided in 2-3 separate doses given during the day or it can be taken as a single dose in the evening, half hour before retiring.
Insomnia caused by anxiety: Initial dose 1mg before going to sleep, usual dose 1-2 mg before going to sleep.
Premedication before operative dentistry or surgery: 2 mg - 4 mg, one to two hours prior to the operation.
Elderly and debilitated patients:
Elderly and debilitated patients may respond to lower doses, and half the normal adult dose or less may be adequate. The starting dose should be half of the recommended adult dose. This initial dose should be adjusted according to clinical response and tolerance.
Children and adolescents:
Lorazepam should not be used in children and adolescents under 18 years of age, as safety and efficacy have not been established in this population, except as indicated below.
Aged 6 years or less:
Children under the age of six should not be treated with lorazepam.
Aged 6 - 12 years:
Premedication before operative dentistry or surgery: 0.5 mg - 1 mg, or 0.05 mg / kg body weight should not be exceeded. The dose should be taken one to two hours prior to the operation.
Aged 13 - 18 years:
Premedication before operative dentistry or surgery: 1-4 mg one to two hours prior to the operation.
Hepatic impairment:
Use in patients with severe hepatic impairment is contraindicated (see section 4.3).
In patients with moderate to mild hepatic impairment, lower doses may be adequate. The starting dose should be half the recommended adult dose. Such patients should be carefully monitored for clinical response and tolerability, and dosage adjusted accordingly (see section 4.4).
Renal impairment:
In patients with severe to mild renal impairment, lower doses may be adequate. The starting dose should be half the recommended adult dose. Such patients should be carefully monitored for clinical response and tolerability, and dosage adjusted accordingly (see section 4.4).
4.3 Contraindications
Hypersensitivity to lorazepam, or to other benzodiazepines, or to any of the excipients (see section 6.1).
Myasthenia gravis.
Severe respiratory insufficiency.
Sleep apnoea syndrome.
Severe hepatic insufficiency.
A history of persistent drug and/or alcohol abuse (see also Section 4.4)
4.4 Special warnings and precautions for use
Use of benzodiazepines, including lorazepam, may lead to potentially fatal respiratory depression.
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, which may be fatal. Patients who develop Angioedema following treatment with a benzodiazepine should not be rechallenged.
Patients should be advised that since their tolerance for alcohol and other CNS depressants will be diminished in the presence of lorazepam, CNS depressants should be avoided or .taken in reduced dosage and alcohol should be avoided. If Lorazepam is taken as a single daily dose in the evening (especially when the dose is high) and the sleep duration is not long enough, there might be a hang-over effect during the following day. Therefore, enough sleep should be ensured (7-8 hours)
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 a more specific treatment.
Abuse of benzodiazepines has been reported, particularly in patients with a history of drug and / or alcohol abuse.
Tolerance:
Some loss of efficacy to the hypnotic effect of benzodiazepines may develop after repeated use for a few weeks. There is evidence that tolerance develops to the sedative effects of benzodiazepines.
Lorazepam may have abuse potential, especially in patients with a history of alcohol and / or drug abuse.
Dependence:
Use of benzodiazepines may lead to the development of physical and psychic dependence upon these products. The risk of dependence increases with the dose and duration of treatment; it is also greater in patients with a history of alcohol or drug abuse, or in patients with significant personality disorders. Therefore use in patients 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 headaches, muscle pain, extreme anxiety, sleep disorders, 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 or epileptic seizures. Seizures may be more common in patients with pre -existing seizure disorders, or who are taking other drugs that lower the seizure 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 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.
After abrupt termination of treatment withdrawal symptoms can occur even after several days of treatment and at therapeutic doses.
Duration of treatment:
The duration of treatment should be as short as possible (see section 4.2) depending on the indication, generally it varies from a few days up to 4 weeks, including the tapering off process. Extension beyond these periods should not take place without re - evaluation of the situation.
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.
When benzodiazepines with a long duration of action are being used it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.
Amnesia:
Benzodiazepines may induce anterograde amnesia. The condition occurs most often 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 section 4.8).
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.
Specific patients 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.
Elderly should be given a reduced dose (see section 4.2). A lower dosage is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression. Benzodiazepines are contraindicated in patients with severe hepatic insufficiency as they may precipitate encephalopathy.
Benzodiazepines are not effective for the primary treatment of psychotic illness.
Benzodiazepines are not effective for the primary treatment of depression and should not be used alone for the treatment of anxiety associated with depression, since suicide could occur in such patients. When administering to severely depressed and suicidal patients it is necessary to take suitable precautions and to prescribe appropriate amounts.
Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse. (See section 4.3)
Some patients taking benzodiazepines have developed blood dyscrasia, and some have had elevated levels of liver enzymes. Periodic haematological and hepatic function assessments are recommended where repeated courses of treatment are considered clinically necessary.
Although hypotension has occurred only rarely, benzodiazepines should be administered with caution in those patients in whom a drop in blood pressure may lead to cardiovascular or cerebrovascular complications; this is of particular importance in elderly patients.
Caution should be used in the treatment of patients with acute narrow angle glaucoma.
Elderly patients should be warned of the risk of falls due to the myelo relaxant effect of lorazepam.
Caution should be used in patients with ataxia and acute intoxication with alcohol or other CNS active agents.
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:
Alcohol: Concomitant alcohol intake should be avoided.
The sedative effects of lorazepam may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or operate machines.
Take into account:
CNS depressants: benzodiazepines, including lorazepam, produce additive CNS depressant effects when co - administered with other drug products that produce CNS depression, e.g. barbiturates, antipsychotics, sedatives / hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anaesthetics.
Muscle relaxants
One should be prepared for an increase of the muscle relaxing effect {risk of falls} when lorazepam is used during therapy with a muscle relaxant, especially during the beginning of treatment with lorazepam.
Narcotic analgesics: enhancement of the euphoria induced by narcotic analgesics may occur with benzodiazepine use, leading to an increase in psychic dependence.
Hepatic enzyme inhibitors: compounds that inhibit certain hepatic enzymes, particularly cytochrome P450, may enhance the activity of benzodiazepines. To a lesser extent this also applies to benzodiazepines that are metabolised by conjugation alone.
Clozapine: concomitant administration has been reported to result in marked sedation, excessive salivation, ataxia, and an increased risk of respiratory and/or cardiac arrest.
Loxapine: concomitant administration has led to reports of excessive stupor, significant reduction in respiratory rate, and in one patient, hypotension.
Sodium valproate: concurrent administration with lorazepam may result in increased plasma concentrations and reduced clearance of lorazepam. Therefore lorazepam dosage should be reduced to approximately 50 % when coadministered with sodium valproate.
Probenecid: concurrent administration with lorazepam may result in a more rapid onset, or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage should be reduced by approximately 50 % when coadministered with probenecid.
Theophylline / Aminophylline: administration may reduce the sedative effects of benzodiazepines, including lorazepam.
4.6 Fertility, pregnancy and lactation
Pregnancy:
There are insufficient data on the use of lorazepam during pregnancy. Benzodiazepines should not be used during pregnancy, especially during the first and last trimesters. Benzodiazepines may cause foetal damage when administered to pregnant women. Based on human experience lorazepam is suggested / suspected to cause an increased risk of congenital malformations when administered during pregnancy, especially during the first trimester of pregnancy. In man, umbilical cord blood samples indicate placental transfer of benzodiazepines and their glucuronide metabolites.
Women of childbearing potential should use effective contraception during treatment with lorazepam. If the drug is prescribed to a woman of childbearing potential, she should be warned to contact her doctor about stopping the medicinal product if she intends to become, or suspects that she is, pregnant.
If, for compelling medical reasons, lorazepam 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. 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.
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.
Lactation:
There is evidence that lorazepam is excreted, albeit in pharmacologically insignificant amounts, in human breast milk. Therefore lorazepam should not be given to breast feeding mothers 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 administered benzodiazepines. Infants of lactating mothers should be observed for pharmacological effects (including sedation and irritability).
4.7 Effects on ability to drive and use machines
Lorazepam has major influence on the ability to drive and use machines. Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the ability to drive or use machines. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased (see also section 4.5). Patients should be warned not to operate machinery, drive, or perform other tasks requiring a high degree of mental alertness.
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:
o The medicine has been prescribed to treat a medicinal or dental problem and
o You have taken it according to the instructions given by the
prescriber and in the information provided with the medicine and o It was not affecting your ability to drive safely
4.8 Undesirable effects
Undesirable effects, 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.
Undesirable effects are listed with the following frequency categories:
|
Very common: |
> 1 / 10 |
Rare: |
> 1 / 10,000 to < 1 / 1,000 |
|
Common: |
> 1 / 100 to < 1 /10 |
Very rare: |
< 1 / 10,000 |
|
Uncommon: |
> 1 / 1,000 |
Not |
Cannot be |
|
to < 1 / 100 |
known: |
estimated from available data |
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Blood and lymphatic system disorders:
Not known: agranulocytosis, pancytopenia, thrombocytopenia, hyponatraemia Immune system disorders:
Not known: anaphylactic / anaphylactoid reactions, angioedema, hypersensitivity reactions, allergic skin reactions
Endocrine disorders:
Not known: Syndrome of Inappropriate Antidiuretic Hormone Hypersecretion (SIADH)
Metabolism and nutrition disorders:
Not known: hypothermia
Psychiatric disorders:
Common: confusion, depression, unmasking of depression
Not known: suicidal ideation / attempt, amnesia, disinhibition, euphoria
Nervous system disorders1:
Very common: sedation / drowsiness Common: ataxia, dizziness
Not known: coma, convulsions / seizures, extrapyramidal symptoms, impaired attention / concentration, balance disorder, vertigo, tremor, headache. Paradoxical reactions including anxiety, agitation, excitation, hostility, aggression, rage, sleep disturbances / insomnia, hallucinations may occur with this product. They are more likely to occur in children and the elderly.
Eye disorders:
Not known: visual disturbances, including diplopia and blurred vision. Vascular disorders:
Not known: hypotension, lowering of blood pressure
Respiratory, thoracic and mediastinal disorders2:
Not known: respiratory depression, apnoea, worsening of sleep apnoea, worsening of obstructive pulmonary disease, Dysarthria / slurred speech
Gastrointestinal disorders:
Uncommon: nausea Not known: constipation
Hepatobiliary disorders:
Not known: jaundice, elevated bilirubin, elevated liver transaminases, elevated alkaline phosphatase
Skin and subcutaneous tissue disorders:
Not known: alopecia
Musculoskeletal and connective tissue disorders:
Common: muscle weakness, asthenia
Reproductive system and breast disorders:
Uncommon: change in libido, impotence, decreased orgasm Not known: sexual arousal
General disorders and administration site conditions;
Very common: fatigue
1 - Benzodiazepine effects on the CNS are dose dependent, with more severe CNS depression occurring with high doses
2 - the extent of respiratory depression with benzodiazepines is dose dependent, with more severe depression occurring with high doses
Pre - existing depression may emerge during benzodiazepine use.
Transient anterograde amnesia or memory impairment may occur using therapeutic doses, the risk increasing at higher doses (see section 4.4). Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rage, nightmares, hallucinations, psychoses, and inappropriate behaviour have been reported occasionally during benzodiazepine use. Such reactions may be more likely to occur in children and the elderly (see section 4.4).
Use, even at therapeutic doses, may lead to physical or psychological dependence and discontinuation of therapy may result in withdrawal reactions or rebound phenomena (see section 4.4). Psychic dependence may occur. Abuse of benzodiazepines has been reported.
4.9 Overdose
General:
As with other benzodiazepines, overdose should not present a threat to life unless combined with other CNS depressants, including alcohol.
In the management of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken. In postmarketing experience, overdose with lorazepam has occurred predominantly in combination with alcohol and / or other medicinal products.
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 where alcohol or other CNS depressant medicinal products are ingested, symptoms may include dysarthria, ataxia, paradoxical reactions, CNS depression, hypotension, hypotonia, respiratory and cardiovascular depression, rarely coma, and very rarely death.
Treatment:
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. Thereafter treatment should be symptomatic and supportive. The patient should be maintained under close observation, with monitoring of vital signs. Special attention should be paid to respiratory and cardiovascular functions in intensive care.
Hypotension, although unlikely, may be controlled with noradrenaline. Lorazepam is poorly dialyzable; lorazepam glucuronide, the inactive metabolite, may be highly dialyzable.
The benzodiazepine antagonist, flumazenil, may be useful in hospitalised patients as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. See flumazenil product information before use. The doctor should be aware of a risk of seizure in association with flumazenil therapy, especially in long term benzodiazepine users and in cyclic antidepressant overdose.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Benzodiazepine derivatives ATC code: N05BA06
Lorazepam is a benzodiazepine drug with short to medium duration of action. It has all the well-known intrinsic benzodiazepine effects: anxiolytic, sedative / hypnotic, anticonvulsant and muscle relaxant, each to a different extent.
5.2 Pharmacokinetic properties
Absorption:
Following oral administration lorazepam is rapidly and almost completely absorbed, peak serum levels occurring at 2 hours (range: 0.5 - 3 h), oral bioavailability 90 - 93 %.
Distribution:
Lorazepam is approximately 85 % - 91 % protein bound, with the free fraction being significantly higher in elderly patients. It penetrates the cerebrospinal fluid, with concentrations being about 5 % - 28 % corresponding plasma levels. It crosses the placental barrier, and plasma levels in neonates approximate maternal serum levels. Distribution half-life is 20 - 25 minutes (range: 10.3 - 42.7), and volume of distribution is 1.3 L / Kg.
Steady state plasma concentrations are achieved within three days.
Metabolism:
Lorazepam is extensively metabolised in the liver, approximately 75 %, and undergoes enterohepatic recirculation, chronic dosing has no effect on hepatic hydroxylation capacity. The principal metabolite, inactive, is 3 - O - phenolic glucuronide at 75 % dose, with smaller amounts of 6 - chloro - 4 - O -chlorophenyl - 2, 1 - quinazolinone, and the hydroxylated derivative of lorazepam, all of which are inactive.
Excretion:
The principal route of excretion is renal, 88 %, with lower amounts excreted in the faeces, 7 %. Total body clearance is 1.1 ml / minute / Kg.
Lorazepam elimination half-life is 12 h and there is minimal risk of excessive accumulation. The elimination half-life of the glucuronide inactive metabolite is 12 - 18 hours.
There is no alteration in the pharmacokinetic parameters in the elderly.
In severe hepatic impairment the elimination half-life of lorazepam is doubled. Renal impairment results in a decrease in rate of glucuronide metabolite excretion without an increase in the half-life of lorazepam.
5.3 Preclinical safety data
Single dose toxicity / Acute toxicity
Acute peroral lorazepam toxicity studies in animals did not reveal any specific sensitiveness (see 4.9 “Overdose” for acute toxicity in man).
Subchronic and chronic toxicity
Peroral lorazepam was investigated in rats (80 weeks) and dogs (12 months) in chronic toxicity studies. Histopathological, ophthalmological, and haematological examinations as well as organ functioning tests showed no or only slightly significant changes without biological relevance, even in high doses
Oesophageal dilation occurred in rats treated with lorazepam for more than one year at a dose of 6 mg / kg / day.
Mutagenic and carcinogenic potential
Lorazepam has not been subjected to extensive studies on mutagenic effects; however, tests on lorazepam were negative hitherto. Studies in rats and mice did not indicate any distinct carcinogenic potential after oral lorazepam application.
Reproduction toxicity
The effect of lorazepam on embryonal and foetal development and reproduction was examined in rabbits, rats and mice. These studies did not reveal any evidence of teratogenic properties or dysfunction of reproduction of lorazepam.
Experimental studies gave evidence of behavioural disorders of the offspring of maternal animals with long-term exposure to benzodiazepines.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate Povidone (K 30)
Crospovidone, Type A Maize starch
Microcrystalline cellulose, E 460 Sodium starch glycolate Polacrilin potassium Magnesium stearate, E 572
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
15 months
Special precautions for storage
6.4
Store below 25oC. Store in original packaging to protect from light.
6.5 Nature and contents of container
Blisters of opaque PVC / PE / PVDC - Aluminium.
Packs containing: 10, 14, 15, 20, 28, 30, 50, 60, 90, 100 and (hospital/pharmacy only) 500 tablets are available.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Morningside Healthcare Ltd
115 Narborough Road, Leicester, LE3 0PA
8 MARKETING AUTHORISATION NUMBER(S)
PL 20117/0162
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
03/12/2012
10 DATE OF REVISION OF THE TEXT
12/05/2014