Revision Year: 2022 Publisher: Medochemie Ltd., 1-10 Constantinoupoleos Street, 3011 Limassol, Cyprus
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.
Concomitant use of lorazepam and opioids may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of sedative medicines such as benzodiazepines or related drugs such as lorazepam with opioids should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe lorazepam concomitantly with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2). The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers (where applicable) to be aware of these symptoms (see section 4.5).
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.
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 whom 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 day of treatment and at therapeutic doses.
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.
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).
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.
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.
Lorazepam should be used with caution in elderly due to the risk of sedation and/or musculoskeletal weakness that can increase the risk of falls, with serious consequences in this population. Elderly patients should be given a reduced dose (see section 4.2).
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, total lactase deficiency or glucose–galactose malabsorption should not take this medicine.
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
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.
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.
The concomitant use of sedative medicines such as benzodiazepines or related drugs such as lorazepam with opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dosage and duration of concomitant use should be limited (see section 4.4).
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.
Enhancement of the euphoria induced by narcotic analgesics may occur with benzodiazepine use, leading to an increase in psychic dependence.
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.
Concomitant administration has been reported to result in marked sedation, excessive salivation, ataxia, and an increase risk of respiratory and/or cardiac arrest.
Concomitant administration has led to reports of excessive stupor, significant reduction in respiratory rate, and in one patient, hypotension.
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.
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 co-administered with probenecid.
Administration may reduce the sedative effects of benzodiazepines, including lorazepam.
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.
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).
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.
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, 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.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Not known: agranulocytosis, pancytopenia, thrombocytopenia, hyponatraemia
Not known: anaphylactic/anaphylactoid reactions, angioedema, hypersensitivity reactions, allergic skin reactions
Not known: Syndrome of Inappropriate Antidiuretic Hormone Hypersecretion (SIADH)
Not known: hypothermia
Common: confusion, depression, unmasking of depression
Not known: suicidal ideation/attempt, amnesia, disinhibition, euphoria
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.
Not known: visual disturbances, including diplopia and blurred vision.
Not known: hypotension, lowering of blood pressure
Not known: respiratory depression, apnoea, worsening of sleep apnoea, worsening of obstructive pulmonary disease, dysarthria/slurred speech
Uncommon: nausea
Not known: constipation
Not known: jaundice, elevated bilirubin, elevated liver transaminases, elevated alkaline phosphatase
Not known: alopecia
Common: muscle weakness, asthenia
Uncommon: change in libido, impotence, decreased orgasm
Not known: sexual arousal
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.
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: ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal.
Not applicable.
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