Central Nervous System-Anxiolytics
Central Nervous System
= Additional active ingredients
Lorazepam 1 mg.
PRESENTATION AND DOSSAGE
TABS: 20 x 1 mg
TABS: 50 x 1 mg
Hypersensitivity to Lorazepam, other benzodiazepines or to any other of the excipients. Acute pulmonary insufficiency: respiratory depression; sleep apnoea (risk of further respiratory depression); Severe respiratory insufficiency; Obsessional states (inadequate evidence of safety and efficacy); Planning a pregnancy; Pregnancy (unless there are compelling reasons); Myasthenia gravis; Severe hepatic insufficiency (may precipitate encephalopathy); Acute narrow-angle glaucoma. Benzodiazepines should not be used alone in anxiety with depression (may precipitate suicide).
Not recommended: Concomitant intake with alcohol – the sedative effects may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines.
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: The benzodiazepines, including lorazepam, produce additive CNS depressant effects when co-administered with other medications which themselves produce CNS depression e.g., barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, neuroleptics, narcotic analgesics, sedative antihistamines, anticonvulsants, and anesthetics. 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. Concurrent administration of lorazepam with sodium valproate may result in increased plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage should be reduced to approximately 50% when coadministered with sodium valproate. Valproate may inhibit the glucuronidation of lorazepam (increased serum levels: increased risk of drowsiness). 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.
Narcotic analgesics: An enhancement of the euphoria induced by narcotic analgesics may occur with benzodiazepine use, leading to an increase in psychic dependence.
Clozapine: There have been reports of marked sedation, excessive salivation, hypotension, delirium, respiratory arrest and ataxia when lorazepam and clozapine have been given concomitantly.
Other drugs enhancing the sedative effect of diazepam: Cisapride, lofexidine, nabilone, disulfiram and the muscle relaxants – baclofen and tizanidine. There have been reports of excessive stupor, significant reduction in respiratory rate and, in one patient, hypotension when lorazepam and loxapine have been given concomitantly.
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 benzodiazepines. The effects of benzodiazepines 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.
Dopaminergics: 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: Administration of theophylline or aminophylline increase metabolism of lorazepam which may reduce the sedative effects of benzodiazepines, including lorazepam.
Probenecid: Concurrent administration of lorazepam with probenecid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid. The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation.
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 mat 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.
Use of benzodiazepines, including lorazepam, both used alone and in combination with other CNS depressants 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 and be fatal. Patients who develop angioedema after treatment with a benzodiazepine should not be rechallenged with the drug. Lorazepam should be used with caution in patients with compromised respiratory function (e.g., COPD). 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. Anxiety 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. Abuse of benzodiazepines has been reported, especially in patients with a history of drug and/or alcohol abuse.
Tolerance: Some loss of efficacy to the hypnotic effects of short-acting 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 drug and/or alcohol abuse.
Dependence: 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. Therefore, the drug should always be discontinued gradually. Withdrawal symptoms can appear following cessation of recommended doses after as little as one week of therapy. Abrupt termination of treatment may be accompanied by withdrawal symptoms. 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 minimize anxiety should they occur. Symptoms reported following discontinuation of benzodiazepines include headaches, muscle pain, anxiety, tension, depression, insomnia, restlessness, dizziness, nausea, diarrhoea, loss of appetite, confusion, hallucinations/delirium, perceptual changes, irritability, dysphoria, convulsions/seizures, tremor, abdominal cramps, myalgia, agitation, palpitations, tachycardia, panic attacks, vertigo, hyperreflexia, short-term memory loss, hyperthermia, 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/perceptual changes, involuntary movements, vomiting, hallucinations, catatonia, convulsions. Convulsions/seizures may be more common in patients with preexisting seizure disorders or who are taking other drugs that lower the convulsive threshold such as antidepressants.
Duration: Treatment should be as short as possible. Generally, the duration of treatment varies from a few days to 4 weeks including the tapering off process. 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 minimize anxiety should they occur. 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: Transient anterograde amnesia or memory impairment has been reported in association with the use of benzodiazepines.
Psychiatric and paradoxical reactions: Paradoxical reactions have been occasionally reported during benzodiazepine. Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued.
Specific patient groups: Lorivan (lorazepam) is not recommended for use in patients with a primary depressive disorder or psychosis. Lorivan 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 Lorivan should not be prescribed to these patients. The use of benzodiazepines in these patients should not be used without adequate antidepressant therapy. Pre-existing depression may emerge or worsen during benzodiazepine use. Patients with impaired renal function or mild to moderate hepatic insufficiency 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. 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. In patients where gastrointestinal or cardiovascular disorders coexist with anxiety, it should be noted that lorazepam has not been shown to be of significant benefit in treating the gastrointestinal or cardiovascular component. Esophageal dilation occurred in rats treated with lorazepam for more than one year at 6 mg/kg/day. The no-effect dose was 1.25 mg/kg/day. The effect was reversible only when the treatment was withdrawn within two months of first observation of the phenomenon. The clinical significance of this is unknown. However, use of lorazepam for prolonged periods and in geriatric patients requires caution, and there should be frequent monitoring for symptoms of upper G.I. disease. Safety and effectiveness of lorazepam in children of less than 12 years have not been established.
Geriatric Use: Clinical studies of lorazepam generally were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects; however, the incidence of sedation and unsteadiness was observed to increase with age. Age does not appear to have a significant effect on lorazepam kinetics
Very common: sedation, fatigue, drowsiness.
Common: Asthenia, muscle weakness, Ataxia, dizziness, unsteadiness, confusion, depression, unmasking of depression. Pre-existing depression may emerge during benzodiazepine use. The incidence of sedation and unsteadiness increased with age. Transient anterograde amnesia or memory impairment may occur using therapeutic doses, the risk increasing at higher doses.
Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rage, nightmares, hallucinations, psychoses, and inappropriate behaviour have been occasionally reported during benzodiazepine use. Such reactions may be more likely to occur in children and the elderly. Use (even at therapeutic doses) may lead to physical or psychological dependence and discontinuation of treatment may result in withdrawal reactions or rebound phenomena. Drug withdrawal symptoms.
Adults: 1-4 mg daily in divided doses;
Elderly and debilitated patients: may respond to lower doses and half the normal adult dose or less may be sufficient. This initial dose should be adjusted as needed and tolerated.
Children (under the age of 13 years): Lorazepam is not intended for the treatment of children under the age of 13 years.
Patients with Renal or Hepatic impairment: Lower doses may be sufficient in patients with impaired renal function or mild to moderate hepatic insufficiency. Use in patients with severe hepatic insufficiency is contraindicated.
In the management of overdosage with any drug, 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 drugs. 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 dysarthria, hypnotic state, ataxia, paradoxical reactions, CNS depression, hypotension, hypotonia, respiratory depression, cardiovascular depression, coma, and very rarely, death.
When there is a risk of aspiration, induction of emesis is not recommended. 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. Gastric lavage may be indicated in symptomatic patients. If there is no advantage in emptying the stomach, activated charcoal may be effective in reducing drug absorption. Hypotension, though unlikely usually may be controlled with noradrenaline. Lorazepam is poorly dialysable. Lorazepam glucuronide, the inactive metabolite, may be highly dialysable.
The benzodiazepine antagonist, flumazenil may be useful in hospitalised patients as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. 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 cyclic antidepressant overdose.
PREGNANCY & LACTATION
Reproductive studies in animals were performed in mice, rats, and two strains of rabbits. Occasional anomalies (reduction of tarsals, tibia, metatarsals, malrotated limbs, gastroschisis, malformed skull, and microphthalmia) were seen in drug-treated rabbits without relationship to dosage. Although all of these anomalies were not present in the concurrent control group, they have been reported to occur randomly in historical controls. At doses of 40 mg/kg and higher, there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen at lower doses. The clinical significance of the above findings is not known. Benzodiazepines should not be used during pregnancy, especially during the first and last trimesters. Benzodiazepines may cause fetal damage when administered to pregnant women. In particular, an increased risk of congenital malformations associated with the use of benzodiazepines during the first trimester of pregnancy has been suggested in several studies. In humans, umbilical cord blood samples indicate placental transfer of benzodiazepines and their glucuronide metabolites.
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. 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 can be expected due to the pharmacological action of the compound. 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.
There is evidence that Lorazepam is excreted, albeit in pharmacologically insignificant amounts, in human breast milk. Therefore, Lorivan should not be given to breastfeeding 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 taking benzodiazepines. Infants of lactating mothers should be observed for pharmacological effects (including sedation and irritability).
MANUFACTURER & DISTRIBUTER:
Manufacturer: Dexcel Ltd.
License Holder: Dexcel Ltd.