Lorazepam 1mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Lorazepam 1mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Lorazepam 1mg Tablets contain 1mg of the active ingredient lorazepam. Lorazepam (INN, BAN) is chemically defined as 7-chloro-5-(0-chlorphenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one.
3 PHARMACEUTICAL FORM
Lorazepam 1mg Tablets are blue, capsule-shaped tablets, measuring approximately 4 x 8mm, plain on one face and ‘gp’ breakbar ‘19’ on the other.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
FOR SHORT TERM (2-4 weeks only) USE (adults only)
• Symptomatic relief of anxiety that is severe, disabling or subjecting the individual to unacceptable distress occurring alone or in association with insomnia or shortterm psychometric, organic or psychotic illness.
AS PREMEDICATION (adults and children 5 years and above)
Before operative dentistry and general surgery
NOT FOR USE
• Long term (i.e. longer than 4 weeks)
• For mild/moderate anxiety
• For insomnia or anxiety in children
4.2. Posology and method of administration
Route of administration: oral
Treatment to be given:
• Under close medical supervision
• At the lowest effective dose
• For the shortest possible duration (not exceeding 4 weeks)
Doses should be individualised
Extension of use should not take place without further clinical evaluation Chronic use not recommended (little is know of the long term safety and efficacy; potential for dependence-see section 4.4
When treatment is started the patient should be informed that
• treatment will be of limited duration
• the dosage will be progressively decreased
• there is a possibility of rebound phenomena
Dosage:
Adults:
Anxiety: 1-4mg daily in divided doses.
Insomnia: 1-2mg before retiring
Premedication before operative dentistry or general surgery:
2-3mg the night before operation 2-4mg one to two hours before the procedure
Elderly:
The elderly may respond to lower doses (half normal adult dose or less)
Children (aged 5-13 years):
Premedication: 0.5-2.5mg at 0.05mg/kg to the nearest 0.5mg according to weight, not less than one hour before operation.
Patients with Renal or Hepatic impairment:
Lower doses may be sufficient in these patients (See section 4.4). Use in patients with severe hepatic insufficiency is contraindicated. (See section 4.6)
4.3. Contraindications
• Hypersensitivity to benzodiazepines or to any of the other ingredients
• Acute pulmonary insufficiency: respiratory depression; sleep apnoea (risk of further respiratory depression)
• Obsessional states (inadequate evidence of safety and efficacy)
• Severe hepatic insufficiency (may precipitate encephalopathy)
• Planning a pregnancy (see section 4.6)
• Pregnancy (unless there are compelling reasons- see section 4.6)
• Myasthenia gravis;
Benzodiazepines should not be used alone in depression or anxiety with depression (may precipitate suicide)
4.4. Special warnings and precautions for use
Patients should be advised that since their tolerance for alcohol and other CNS depressants will be diminished in the presence of Lorazepam, these substances should either be avoided or taken in reduced dosage.
Lorazepam 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. Therefore, large quantities of Lorazepam should not be prescribed to these patients.
Pre-existing depression may emerge during benzodiazepine use.
The use of benzodiazepines 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.
Dependence may lead to withdrawal symptoms, especially if treatment is discontinued abruptly. (see 4.8 Undesirable effects). Therefore, the drug should always be discontinued gradually.
It may be useful to inform the patient that treatment will be of limited duration and that it will be discontinued gradually. The patient should also be made aware of the possibility of "rebound" phenomena to minimise anxiety should they occur.
Abuse of benzodiazepines has been reported.
Some loss of efficacy to the hypnotic effects of short-acting benzodiazepines may develop after repeated use for a few weeks.
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.
Caution should be used in the treatment of patients with acute narrow-angle glaucoma.
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 same precautions apply to elderly or debilitated patients and patients with chronic respiratory insufficiency.
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.
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.
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. However, if Lorazepam is used for insomnia due to anxiety, patients should ensure that they will be able to have a period of uninterrupted sleep which is sufficient to allow dissipation of drug effect (e.g., 7-8 hours).
Paradoxical reactions 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 drug should be discontinued (see Undesirable effects).
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.
Contains 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 Alcohol
Lorazepam should not be used together with alcohol (enhanced sedative effects; impaired ability to drive/operate machinery)
Sodium oxybate
Avoid concomitant use (enhanced effects of sodium oxybate)
HIV-protease inhibitors
Avoid concomitant use (increased risk of prolonged sedation - see below for zidovudine
Take into account
Centrally acting drugs
Enhancement of the central depressive effect may occur if lorazepam is combined with drugs such as neuroleptics, antipsychotics, tranquillisers, antidepressants, hypnotics, analgesics, anaesthetics, barbiturates and sedative antihistamines. The elderly may require special supervision.
Anti-epileptic drugs
Pharmacokinetic studies on potential interactions between benzodiazepines and antiepileptic drugs have produced conflicting results. Both depression and elevation of drug levels, as well as no change have been reported.
Phenobarbital taken concomitantly may result in an additive CNS effect. Special care should be taken in adjusting the dose in the initial stages of treatment.
Side effects may be more evident with hydantoins or barbiturates
Valproate may inhibit the glucuronidation of lorazepam (increased serum levels: increased risk of drowsiness)
Narcotic analgesics
Enhancement of the euphoria may lead to increased psychological dependence
Clozapine
Reports of marked sedation, excessive salivation, hypotension, ataxia, delirium and respiratory arrest when given concurrently with lorazepam.
Other drugs enhancing the sedative effect of diazepam
Cisapride, lofexidine, nabilone, disulfiram and the muscle relaxants - baclofen and tizanidine
Compounds that affect hepatic enzymes (particularly cyctochrome P450)
• Inhibitors (e.g. cimetidine, isoniazid; erythyromycin; omeprazole; esomeprazole) reduce clearance and may potentiate the action of benzodiazepines. Itraconazole, ketoconazole and to a lesser extent fluconazole and voriconazole are potent inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may increase plasma levels of benzodiazapines. The effects of benzodiazapines may be increased and prolonged by concomitant use. A dose reduction of the benzodiazepine may be required.
• Inducers (e.g. rifampicin) may increase clearance of benzodiazepines
Antihypertensives, vasodilators and diuretics: Enhanced hypotensive effect with ACE-inhibitors, alpha-blockers, angiotensin-II receptor antagonists, calcium channel blockers, adrenergic neurone blockers, beta-blockers, moxonidine, nitrates, hydralazine, minoxidil, sodium nitroprusside and diuretics
Enhanced sedative effect with alpha-blockers or moxonidine.
Dopamionergics
Possible antagonism of the effect of levodopa
Antacids
Concurrent use may delay absorption of lorazepam
Zidovudine
Increased zidovudine clearance by lorazepam
Oestrogen-containing contraceptives
Possible inhibition of hepatic metabolism of lorazepam
Theophylline/aminophylline
Increases metabolism of lorazepam which possibly reduces the effect
Caffeine
Concurrent use may result in reduced sedative and anxiolytic effects of lorazepam.
Grapefruit juice
Inhibition of CYP3A4 may increase the plasma concentration of lorazepam (possible increased sedation and amnesia).This interaction may be of little significance in healthy individuals, but it is clear is if other factors such as old age or liver cirrhosis increase the risk of adverse events with concurrent use.
4.6 Fertility, pregnancy and lactation
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.
If the drug is prescribed to a woman of childbearing potential, she should be warned to contact her physician about stopping the drug if she intends to become, or suspects that she is, pregnant.
There is a possibility that infants born to mothers who take benzodiazepines chronically during the later stages of pregnancy may develop physical dependence. 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, 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.
Lactation: Lorazepam is excreted in small amounts in breast milk. Mothers who are breast-feeding should not take benzodiazepines. Sedation and inability to suckle have occurred in neonates of lactating mothers taking benzodiazepines.
4.7 Effects on Ability to Drive and Use Machines
Patients should be advised that sedation, amnesia, impaired concentration, dizziness, blurred vision and impaired muscular function may occur and that, if affected, they should not drive or to use machines, or take part in other activities where this would put themselves or others at risk. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased. Concurrent medication may increase these effects (see section 4.5)
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, 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 associated with benzodiazepines include daytime drowsiness, dizziness, muscle weakness, and ataxia.
Adverse reactions are listed by frequency:
Very common (>1/10); Common (>1/100 to <1/10); Uncommon (>1/1,000 to <1/100); Rare (>1/10,000 to <1/1,000); Very rare (<1/10,000); not known (cannot be estimated from the available data)
Blood and lymphatic system disorders
Very rare: Thrombocytopenia, leucopenia, agranulocytosis, pancytopenia Immune system disorders
Very rare: Hypersensitivity including anaphylaxis/anaphylactoid reactions Endocrine disorders
Very rare: Inappropriate antidiuretic hormone secretion, hyponatraemia Psychiatric disorders
Rare: Confusion, depression and unmasking of depression, numbed emotions, disinhibition, euphoria, appetite changes, sleep disturbance, change in libido, decreased orgasm.
Unknown: Dependence, Suicidal ideation/attempt
Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rage, insomnia, nightmares, hallucinations, psychoses, sexual arousal, and inappropriate behaviour have been occasionally reported during use.
Nervous system
Very common: Daytime drowsiness, sedation Common: Dizziness, ataxia
Rare: headache, reduced alertness, dysarthria/slurred speech, transient anterograde amnesia or memory impairment.
Very rare: Tremor, extrapyramidal reactions, Coma (see 4.9 Overdose)
Eye disorders
Rare: Visual disturbances (diplopia, blurred vision)
Vascular disorders
Rare: Hypotension (see 4.4 Special warnings and precautions)
Respiratory thoracic and mediastinal disorders:
Rare: Apnoea, worsening of sleep apnoea, worsening of obstructive pulmonary disease. Respiratory depression (see 4.9 Overdose).
Gastrointestinal disorders
Rare: Nausea, constipation, salivation changes
Hepatobiliary disorders
Rare: Abnormal liver function test values (increases in bilirubin, transaminases, alkaline phosphatise), jaundice
Skin and subcutaneous tissue disorders Rare: Rash, allergic dermatitis
Musculoskeletal disorders Common: Muscle weakness
Reproductive system and breast disorders Rare: Impotence
General disorders Common: Asthenia, fatigue Very rare: Hypothermia
Drug withdrawal symptoms (see 4.4 Special warnings and precautions) 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 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; tinnitus; numbness and tingling of the extremities; hypersensitivity to light, noise, and physical contact; involuntary movements; hyperreflexia, tremor, nausea, vomiting; diarrhoea, abdominal cramps, loss of appetite, agitation, palpitations, tachycardia, panic attacks, vertigo, short-term memory loss, hallucinations/delirium; catatonia; hyperthermia, convulsions. Convulsions 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.
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 at: www.mhra.gov.uk/yellowcard 4.9. Overdose
In the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken.
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 drugs or alcohol are ingested, symptoms may include ataxia, hypotension, hypotonia, respiratory depression, coma, and very rarely, death.
If ingestion was recent, induced vomiting and/or gastric lavage should be undertaken 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 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.
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic Properties
Lorazepam is a benzodiazepine with anxiolytic, sedative and hypnotic properties.
5.2. Pharmacokinetic Properties
Lorazepam is almost completely absorbed from the gastrointestinal tract and peak serum levels are reached in 2 hours. It is metabolised by a simple one-step process to a pharmacologically inert glucuronide. There are no major active metabolites. The elimination half-life is about 12 hours and there is minimal risk of excessive accumulation.
5.3. Pre-clinical Safety Data
Oesophageal dilation occurred in rats treated with lorazepam for more than one year at 6mg/kg/day.
6. PHARMACEUTICAL PARTICULARS 6.1. List of Excipients
Lactose 72 mesh, Lactose powdered anhydrous, microcrystalline cellulose, polacrilin potassium, magnesium stearate, Colouring: E132.
Incompatibilities
6.2.
None known.
6.3. Shelf Life
24 months.
6.4. Special Precautions for Storage
Store in a cool, dry place.
6.5. Nature and Content of Container
1. Blister packs of PVC backed by hard tempered aluminium foil: Pack sizes of 28, 30, 56, 60 or 100 tablets.
2. Opaque polypropylene Securitainers with opaque polythene caps: Pack sizes of 28, 30, 56, 60, 100, 500 or 1000 tablets.
3. Amber glass bottles with screw caps: Pack sizes of 28, 30, 56, 60, 100, 500 or 1000 tablets.
6.6. Instructions for Use, Handling and Disposal
None stated.
7 MARKETING AUTHORISATION HOLDER
Genus Pharmaceuticals Holdings Limited
T/A Genus Pharmaceuticals
Linthwaite
Huddersfield
HD7 5QH, UK
8. MARKETING AUTHORISATION NUMBER
PL 17225/0010
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
1 September 1999
10 DATE OF REVISION OF THE TEXT
16/01/2015