pms-Lorazepam

Lorazepam.

Each tablet contains 0.5 mg, 1 mg or 2 mg lorazepam.
Common name: Lorazepam.
Chemical name: 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one.
Molecular formula and molecular mass: C₁₅H₁₀Cl₂N₂O₂, 321.16 g/mol.
Physicochemical properties: Description: Lorazepam is a white or practically white, practically odorless powder. It is insoluble in water; sparingly soluble in alcohol; slightly soluble in chloroform.
Melting point: 166°C - 168°C.
pK values: pK₁: 13, pK₂: 11.5.
Excipients/Inactive Ingredients: Lactose, Magnesium Stearate, Microcrystalline Cellulose, and Polacrilin Potassium.

Pharmacology: Mechanism of Action: pms-LORAZEPAM (lorazepam) is an active benzodiazepine with a depressant action on the central nervous system. It has anxiolytic and sedative properties which are of value in the symptomatic relief of pathologic anxiety in patients with anxiety disorders giving rise to significant functional disability but is not considered indicated in the management of trait anxiety.
In laboratory animals, lorazepam produces disinhibitory, sedative, anti-convulsant, muscle relaxant, ataxic and hypnotic effects.
Lorazepam has also been shown to possess anticonvulsant activity.
Anterograde amnesia, a lack of recall of events during period of drug action, has been reported and appears to be dose-related.
Pharmacodynamics: Studies with lorazepam in rats demonstrated a decrease in treadmill avoidance without modifying the escape response, an increase in responding during the shock schedule in the conflict test, an increase in incorrect responses in a discrimination test, and a reduction of conditioned suppression if lorazepam was given prior to the fear conditioning trial, while increasing conditioned suppression, if given prior to re-testing. These effects were observed at doses from 0.05 to 20 mg/kg i.p. In some of the tests, diazepam was also used with similar results obtained at approximately 2-5 times the lorazepam dose.
Lorazepam was the most potent of several benzodiazepines tested in affecting state-dependent learning in trained, hungry rats rewarded with sweetened milk and conditioned to simple fear responses by mild electric shock. While 70-75% inhibition of conditioned fear was achieved with intraperitoneal doses of 0.9 mg/kg of lorazepam on the training day, 2.7 mg/kg of diazepam and 5 mg/kg of either chlordiazepoxide or oxazepam were required to obtain similar results. Consistent with state-dependent learning interpretations, a second injection of lorazepam administered to rats just prior to being tested for fear retention fully reinstated the conditioned suppression response.
Daily intraperitoneal injections of lorazepam, diazepam, oxazepam, chlordiazepoxide, scopolamine, or amobarbital, after initially interfering with feeding behaviour, later facilitated it. Following fear conditioning of the animals, all of the drugs, with the exception of scopolamine, increased conditioned suppression in the retention test. These repeated dose experiments, which permit tolerance of depressant side effects to develop, make it unlikely that benzodiazepines or amobarbital increase conditioned suppression retention through some depressant side effect.
In rats, fear-conditioned by electric shocks of different intensities, lorazepam increased retention-test drinking latencies of strongly shocked rats more than it did those of rats given shocks of intermediate or weak intensities.
In mice, lorazepam prevented pentylenetetrazol-induced convulsions at low doses (ED₅₀-0.07 mg/kg p.o.), while much higher doses (0.5-5.0 mg/kg p.o.) were required to raise the threshold to electroshock-induced convulsions. It was demonstrated that lorazepam was more potent than diazepam in antagonizing pentylenetetrazol-induced convulsions by all three routes tested: oral, intraperitoneal, and intravenous. Lorazepam also inhibited the stimulation caused by morphine. Both lorazepam and clonazepam had ED₅₀s for the antagonism of convulsions of less than 1 mg/kg when they were given intravenously or orally only 1 minute before the pentylenetetrazol challenge.
Observations of monkeys provided strong evidence of the sedative action of lorazepam. Here, relatively high doses of lorazepam caused brief initial depression followed by long periods of obvious sedation.
The behaviour of cats and mice, after receiving lorazepam supported these findings. In mice, it was shown that lorazepam is a more potent sedative than diazepam or flurazepam.
Its ability to inhibit foot shock induced fighting between mice, together with reactions of rats and squirrel monkeys in a series of conflict tests considered specific predictors of anti-anxiety activity, confirmed the anxiolytic potential of lorazepam.
The general depressant effects of repeated dosings of lorazepam in rats diminished rapidly while its anticonflict action remained, findings suggesting that while the anti-anxiety effects of lorazepam endure, any behaviour disruption is transitory.
Doses of 5 to 50 mg/kg I.V. caused ataxia and obvious CNS depression in rhesus monkeys, lasting for over 5 hours at the highest dose. Suppression of the linguomandibular reflex was demonstrated in anaesthetized cats suggesting a central muscle-relaxant effect of lorazepam in this species. Higher doses, however, were required than with diazepam to produce significant reflex inhibition.
Using suppression of linguomandibular reflexes in cats as a measure of centrally mediated muscle relaxation, it was demonstrated that intravenous doses of 0.25 to 2 mg/kg of lorazepam were active in a dose-related manner, that the patellar reflex was not suppressed indicated a preferential effect on polysynaptic pathways.
Studies on the cardiovascular system in anaesthetized animals demonstrated that lorazepam, at a dose of 0.1 mg/kg, given by intraperitoneal injection had little effect on either blood pressure or heart rate. Second injections of 0.9 mg/kg one hour later caused some depression of cardiovascular parameters of anaesthetized cats and dogs. Doses greater than 0.9 mg/kg resulted in an average decrease of approximately 40% in both blood pressure and heart rate. Electrocardiograms taken near the conclusion of a 33-34 day study in which beagle dogs received daily intramuscular injections of lorazepam showed only slight increases in the heart rates of both vehicle control and drug-treated animals.
Clinical Trials: The clinical trial data on which the original indication was authorized is not available.
Comparative Bioavailability Studies: A bioavailability study comparing two different formulations of lorazepam was performed. Pharmacokinetic and bioavailability data of pms-LORAZEPAM were measured from volunteers in the fasting state after a single 4 mg (2 x 2 mg tablets) dose of pms-LORAZEPAM was administered. The results can be summarized as follows: See Table 1.

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Pharmacokinetics: The serum half-life of lorazepam ranges between 12 to 15 hours, while that of the conjugate varied between 16 to 20 hours.
Absorption: Lorazepam is rapidly absorbed after oral administration, with mean peak plasma concentrations of free lorazepam at 2 hours (range between 1-6 hours). Following intravenous administration, peak plasma levels are reached within minutes, whereas following administration by the intramuscular route, peak plasma levels occur between 60 to 90 minutes. After sublingual administration, peak plasma levels occur at 60 minutes. By the intramuscular route, the absorption half-life values of lorazepam average 12 and 19 minutes, whereas by the oral route, there is an additional lag period averaging 15 and 17 minutes. Bioavailability was shown to be identical by all routes of administration.
Lorazepam is rapidly conjugated to a glucuronide which has no demonstrable psychopharmacological activity and is excreted mainly in the urine. Very small amounts of other metabolites and their conjugates have been isolated from urine and plasma.
Distribution: Except for the organs of absorption and excretion, tissue distribution of ¹⁴C-lorazepam in rats was nearly uniform.
Metabolism: Metabolic studies in mice, rats, cats, dogs and miniature swine were conducted on the absorption, excretion, tissue distribution and biotransformation of lorazepam. Both ¹⁴C-labelled and unlabelled drug was used. The most important finding was the conjugation of lorazepam with glucuronic acid in all investigated species. Lorazepam glucuronide, essentially inactive as an anti-anxiety agent, accounted for most of the drug-related urinary excretion products in all species except the rat in which, in addition to glucuronide formation, more extensive biotransformation took place.
Elimination: Most of the drug (88%) is excreted in the urine, with 75% excreted as the glucuronide. At the clinically relevant concentrations, approximately 85% of lorazepam is bound to plasma proteins.
Maximum concentrations of unchanged lorazepam in whole blood and plasma of rats occurred one-half to one hour after oral drug administration, and these concentrations declined to low levels within 24 hours. In dogs and miniature swine, concentrations of orally administered lorazepam peaked and declined rapidly, but they consisted principally of lorazepam glucuronide. These findings correlated with the rapid elimination observed in dogs administered lorazepam intravenously when no free drug was detected in plasma six hours later, and the half-life was estimated to be 1.6 hours. The major route of lorazepam excretion for the dog and the miniature swine is by the kidneys. Biliary excretion has been demonstrated in the rat.
Species differences in urinary excretion patterns were investigated qualitatively in the mouse, rat, cat, dog, and miniature swine. The major urinary excretion product was the glucuronide conjugate of lorazepam. In dogs, the pattern of biotransformation of lorazepam seemed independent of dose; in rats, it appeared dose-dependent and produced significant amounts of several metabolites rather than the predominance of glucuronide found in other species, including the human. No sex differences were noted in the urinary excretion patterns of the several species tested. Peak urinary excretion was noted at 2-6 hours and total recovery in urine and feces over 48 hours was as high as 100% in some species.
Special Populations and Conditions: The special populations and conditions pharmacokinetics data on which the original indication was authorized is not available.
Toxicology: Non-clinical Toxicology: General Toxicology: Acute Toxicity: Oral. LD₅₀s ranged from 1,850-5,010 mg/kg in mice to 5,000 mg/kg in rats and 2,000 mg/kg in dogs. The intraperitoneal LD₅₀s were 700 mg/kg in rats and mice. In newborn rats and mice, intragastric LD₅₀ values were 200 and 250 mg/kg respectively.
Signs exhibited during acute toxicity testing included moderate to marked sedation, shortness of breath, paralysis of hind legs, loss of righting reflex and convulsions. Acute respiratory depression was noted as the mode of death.
Injectable. The acute toxicity of lorazepam in adult mice and rats were determined to be: See Table 2.

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In beagle dogs, the approximate LD₅₀ for intravenous lorazepam was 50 mg/kg (equivalent to 10 mL/kg). The highest intramuscular dose of lorazepam that, because of its volume, could be given to dogs was 25 mg/kg (equivalent to 5 mL/kg). The toxicity of injectable lorazepam in all three species seemed due almost entirely to the vehicle employed.
Long-Term Toxicity: Oral. Lorazepam was administered in the diet to rats in a number of studies extending for periods of 4 to 82 weeks at doses ranging from 14.5 to 400 mg/kg/day. In the long-term studies, decreased food consumption and body weight gain were observed at the higher dose levels, while at lower dose levels weight gain tended to be increased relative to controls. Transient, dose-related sedation and ataxia also occurred, and convulsions were noted, particularly following drug withdrawal. The only gross pathological finding was esophageal dilatation, which was observed in a number of animals at different dose levels. This condition also occurred with diazepam, and the significance of this finding is at present unknown.
Increased liver, kidney, thyroid, adrenal and testicular weights, as well as centrilobular hypertrophy of the liver, cloudy swelling and loss of glycogen were observed in drug-treated animals. At the highest dose levels, changes in the nuclei of the hypertrophied liver cells also occurred. In one study, the colloid follicles of the thyroid were lined with tall cells and were reported to be increased in a dose-related manner. Effects on blood chemistry included increases in serum protein and cholesterase levels and a decrease in serum alkaline phosphatase. These changes were observed mostly at the higher dose levels and were more marked in females. Three oral studies were conducted in dogs, ranging from 6 to 52 weeks in duration at doses of up to 480 mg/kg/day. A high incidence of emesis occurred in the early stages of the studies. Most drug treated dogs exhibited the following signs: sedation, ataxia, tremors, restlessness, excitement, apprehension, salivation, panting, vocalization, muscle weakness and depression; of these only sedation persisted. Polydipsia was also observed.
There were some increases in spleen, liver and testicular weight, and, at the highest dose, serum alkaline phosphatase and hematocrit values were elevated. Increased platelet and cholesterol values were also noted in the long-term study.
Injectable. In two studies in adult rats, lorazepam was administered either intravenously for ten days or intramuscularly for 33 to 37 days. Food consumption and body weight gain were little affected.
Most animals were sedated to some extent, and even ataxic at the high doses. Statistically significant differences to hematologic values between treated and control animals of both studies were within normal limits. With the possible exception of decreases in serum glucose in the second study, all serum chemical differences were small and considered biologically unimportant. Ophthalmoscope examinations made in both studies revealed no ocular abnormalities.
Some organ weights of lorazepam-treated animals differed significantly from those of control animals, but there was no consistent pattern to the variations.
Histopathologic examinations at the end of both studies revealed marked tissue reactions at the injection sites of rats treated with either lorazepam or vehicle alone. The only other pathological change thought to be related to treatment was an unusual degree of extramedullary splenic hematopoiesis, a condition confined chiefly to high-dose animals of Study 2. There were no accompanying changes in bone marrow or lymphoid tissues.
Purebred beagle dogs received daily intramuscular injections of 2.5, 5.0 or 10.0 mg/kg of lorazepam for 33-34 days. Their behaviour was only mildly and occasionally affected; appetite and mean body weight changes were similar in treated and untreated dogs. The drug-treated animals drank more water. There were episodes of emesis, and occasionally some stools were loose. Injection site sores developed on drug-treated and vehicle control dogs. Electrocardiograms taken near the study's conclusion showed slight increases in heart rate of vehicle control and lorazepam-treated animals. Alterations in several hematologic parameters in lorazepam-treated and vehicle control dogs were attributed to loss of blood and inflammatory reactions at injection sites. Statistical analysis of group mean blood chemical values showed several significant differences in mid and high-dose lorazepam dogs and those given the vehicle only. With the possible exception of elevated cholesterol, SGPT, and SGOT values, these differences were small and believed to be of no biological importance. The elevated SGOT levels were attributed to injection site inflammation. While some changes were suggestive of liver involvement, no histological alterations to that organ were discovered. Marked inflammatory injection site reactions were found on all dogs treated with lorazepam or its vehicle. Splenic hematopoiesis occurred in varying degrees among drug-treated and vehicle control animals. Hypercellularity of the bone marrow was discovered in four lorazepam-treated dogs and two vehicle control animals. It is likely this resulted from injection site stress and blood loss.
In anticipation of lorazepam being used concomitantly with other therapeutic agents in a variety of clinical situations, drug interaction studies were undertaken. Lorazepam was without effect on the LD₅₀ of morphine in rats. Although the oral LD₅₀ of lorazepam in mice was not modified by phenelzine, the depressor effect of intravenous lorazepam or diazepam in the presence of phenelzine, was increased in rats. In common with other anxiolytic-sedatives, oral lorazepam in mice reduced the amount of I.V. thiopental required for hypnosis and respiratory arrest.
Oral doses of lorazepam administered daily for 59 days to beagle dogs did not alter the anticoagulant activity of bishydroxycoumarin. In decerebrate cats, the intensity and duration of the skeletal neuromuscular blocking action of gallamine and suxamethonium were unaffected by intravenous doses of either diazepam or lorazepam.
The drug dependency potential of lorazepam (10 mg/kg), diazepam (5 mg/kg) and chlordiazepoxide (20 mg/kg) by several routes of administration was evaluated in normal, barbital-dependent and withdrawn rhesus monkeys. Like chlordiazepoxide and diazepam, lorazepam suppressed signs of barbital withdrawal. In long-term toxicity studies, convulsions were noted, at the high-dose levels, particularly following withdrawal of lorazepam.
The irritant potential of injectable lorazepam was compared with that of diazepam in mice and rabbits. While the degrees of irritation produced by either compound varied with the routes of administration, it appeared that the experimental vehicles were the principle cause of irritation. The degree of hemolytic potential of lorazepam in an experimental vehicle varied from mild to moderate in rabbit blood, and slight to mild in human or dog blood.
Reproductive and Developmental Toxicology: Oral. A number of reproductive studies, covering various stages of the reproductive cycle, were carried out in rats, rabbits and mice. Lorazepam was administered orally in doses of up to 50 mg/kg/day. The observed effects in drug-treated groups of all three species included decreased maternal weight gain, increased resorptions, increased incidence of complete litter loss, decreased litter size, increased number of stillborn, increased neonatal mortality and decreased fetal body weight. Major and minor malformations, including cleft palate, hindlimb malrotation, extra 13th ribs, gastroschisis and major skull deficiency, were noted in rabbit and mouse experiments; some of these were qualitatively similar and/or dose-related, and possibly drug induced.
Developmental Neurotoxicity: Nonclinical research has shown that administration of anesthetic and sedation drugs that block N-methyl-D-aspartate (NDMA) receptors and/or potentiate gamma-aminobutyric acid (GABA) activity can increase neuronal cell death in the brain and result in long term deficits in cognition and behavior of juvenile animals when administered during the period of peak brain development. Based on comparisons across nonclinical species, the window of vulnerability of the brain to these effects is believed to correlate with human exposures in the third trimester of pregnancy through the first year of life, but may extend to approximately 3 years of age. While there is limited information of this effect with lorazepam, since the mechanism of action includes potentiation of GABA activity, a similar effect may occur. The relevance of these nonclinical findings to human use is unknown.
Injectable. Lorazepam, intravenously administered, was studied in rats and rabbits for its possible impact on reproduction and fetal development. Injectable lorazepam was associated to some extent with the number of resorptions, litter sizes and weights in both species, but these effects were neither consistent nor dose related.
In rats and rabbits, injectable lorazepam was not teratogenic.
Microbiology: No microbiological information is required for this drug product.

pms-LORAZEPAM (lorazepam tablets) is indicated for: the short-term relief of manifestations of excessive anxiety in patients with anxiety neurosis; an adjunct for the relief of excessive anxiety that might be present prior to surgical interventions.
Anxiety and tension associated with the stresses of everyday life usually do not require treatment with anxiolytic drugs.
Pediatrics: Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
Geriatrics: Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness.
Long-term use of pms-LORAZEPAM should be avoided in geriatric patients. Enhanced monitoring is recommended (see Neurologic: Falls and Fractures under Precautions; Dosing Considerations under Dosage & Administration).

Dosing Considerations: pms-LORAZEPAM should always be prescribed at the lowest effective dose for the shortest duration possible.
pms-LORAZEPAM can produce withdrawal signs and symptoms or rebound phenomena following abrupt discontinuation or rapid dose reduction (see Withdrawal under Warnings; Dependence/Tolerance under Precautions). Abrupt discontinuation should be avoided and treatment - even if only of short duration - should be terminated by gradually tapering the dosage schedule under close monitoring. Withdrawal symptoms (e.g., rebound insomnia) can appear following cessation of recommended doses after as little as one week of therapy.
Tapering should be tailored to the specific patient. Special attention should be given to patients with a history of seizure.
If a patient experiences withdrawal signs and symptoms, consider postponing the taper or raising the benzodiazepine to the previous dosage prior to proceeding with a gradual taper.
Symptoms reported following discontinuation of benzodiazepines include: headache, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, rebound phenomena, dysphoria, dizziness, derealization, depersonalization, hyperacusis, numbness/tingling of extremities, hypersensitivity to light, noise and physical contact/perceptual changes, involuntary movements, nausea, vomiting, diarrhea, loss of appetite, hallucinations/delirium, convulsions/seizures, tremor, abdominal cramps, myalgia, agitation, palpitations, tachycardia, panic attacks, vertigo, hyperreflexia, short-term memory loss, and hyperthermia. Convulsions/seizures 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.
Renal or hepatic disease: The dose should be titrated should pms-LORAZEPAM be used in patients with mild to moderate hepatic or renal disease. In patients for whom prolonged therapy with pms-LORAZEPAM is indicated, periodic blood counts and liver function tests should be carried out.
When lorazepam is used in patients with mild to moderate hepatic or renal disease, the lowest effective dose should be considered since drug effect may be prolonged. (See Renal under Precautions.)
Geriatrics: For elderly and debilitated patients reduce the initial dose by approximately 50% and adjust the dosage as needed and tolerated. Geriatric patients in particular may be more sensitive to benzodiazepines (see Neurologic: Falls and Fractures under Precautions). Long-term use of pms-LORAZEPAM should be avoided in geriatric patients. Enhanced monitoring is recommended. (See Use in the Elderly under Precautions.)
Recommended Dose and Dosage Adjustment: The dosage and duration of therapy of pms-LORAZEPAM must be individualized and carefully titrated in order to avoid excessive sedation or mental and motor impairment.
As with other anxiolytic sedatives, short courses of treatment should usually be the rule for the symptomatic relief of disabling anxiety in psychoneurotic patients and the initial course of treatment should not last longer than one week without reassessment of the need for a limited extension.
Initially, not more than one week's supply of the drug should be provided, and automatic prescription renewals should not be allowed. Subsequent prescriptions, when required, should be limited to short courses of therapy. (See Withdrawal under Warnings; Dependence/Tolerance under Precautions.)
Generalized Anxiety Disorder: The recommended initial adult daily oral dosage is 2 mg in divided doses of 0.5, 0.5 and 1 mg, or of 1 mg and 1 mg. The daily dosage should be carefully increased or decreased by 0.5 mg depending upon tolerance and response. The usual daily dosage is 2 to 3 mg. However, the optimal dosage may range from 1 to 4 mg daily in individual patients. Usually, a daily dosage of 6 mg should not be exceeded.
In elderly and debilitated patients, the initial daily dose should not exceed 0.5 mg and should be very carefully and gradually adjusted, depending upon tolerance and response.
Excessive Anxiety Prior to Surgical Procedures: Adults: As with all premedicant drugs, the dose should be individualized. Doses of other central nervous system depressant drugs should be ordinarily reduced.
Health Canada has not authorized an indication for pediatric use.
Missed Dose: Patients who miss taking a dose should contact their healthcare provider for instructions.

In post-marketing experience, overdose with lorazepam has occurred predominantly in combination with alcohol and/or other drugs.
Symptoms: With benzodiazepines, including lorazepam, symptoms of mild overdosage include drowsiness, mental confusion and lethargy. In more serious overdoses, symptoms may include ataxia, hypotonia, hypotension, hypnosis, Stages I to III coma, and, very rarely, death. Symptoms can range in severity and include, in addition to the previously mentioned, dysarthria, paradoxical reactions, CNS depression, respiratory depression, and cardiovascular depression.
Treatment: In the case of an oral overdose, if vomiting has not occurred spontaneously and the patient is fully awake, emesis may be induced with syrup of ipecac 20-30 mL (where there is risk of aspiration, induction of emesis is not recommended). Gastric lavage should be instituted as soon as possible and 50-100 g of activated charcoal should be introduced to and left in the stomach.
Lorazepam is poorly dialyzable. Lorazepam glucuronide, the inactive metabolite, may be highly dialyzable.
General supportive therapy should be instituted as indicated. Vital signs and fluid balance should be carefully monitored. An adequate airway should be maintained and assisted respiration used as needed. With normally functioning kidneys, forced diuresis with intravenous fluids and electrolytes may accelerate elimination of benzodiazepines from the body. In addition, osmotic diuretics such as mannitol may be effective as adjunctive measures. In more critical situations, renal dialysis and exchange blood transfusions may be indicated. Published reports indicate that intravenous infusion of 0.5 to 4 mg of physostigmine at the rate of 1 mg/minute may reverse symptoms and signs suggestive of central anticholinergic overdose (confusion, memory disturbance, visual disturbances, hallucinations, delirium); however, hazards associated with the use of physostigmine (i.e., induction of seizures) should be weighed against its possible clinical benefit.
The benzodiazepine antagonist flumazenil may be used in hospitalized patients as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. The physician should be aware of the risk of a seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose.
For management of a suspected drug overdose, contact the regional poison control centre.

pms-LORAZEPAM (lorazepam tablets) is contraindicated in patients with myasthenia gravis or acute narrow angle glaucoma and in those with known hypersensitivity to benzodiazepines.
pms-LORAZEPAM is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Description.

Addiction, Abuse and Misuse: The use of benzodiazepines, including pms-LORAZEPAM can lead to abuse, misuse, addiction, physical dependence and withdrawal reactions. Abuse and misuse can result in overdose or death, especially when benzodiazepines are combined with other medicines, such as opioids, alcohol or illicit drugs.
Assess each patient's risk prior to prescribing pms-LORAZEPAM.
Monitor all patients regularly for the development of these behaviours or conditions.
pms-LORAZEPAM should be stored securely to avoid theft or misuse.
Withdrawal: Benzodiazepines, like pms-LORAZEPAM can produce severe or life-threatening withdrawal symptoms.
Avoid abrupt discontinuation or rapid dose reduction of pms-LORAZEPAM.
Terminate treatment with pms-LORAZEPAM by gradually tapering the dosage schedule under close monitoring (see Dependence/Tolerance under Precautions).
Risks from Concomitant Use with Opioids: Concomitant use of pms-LORAZEPAM and opioids may result in profound sedation, respiratory depression, coma and death (see Concomitant Use with Opioids under Precautions).
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Limit dosages and durations to the minimum required.
Follow patients for signs and symptoms of respiratory depression and sedation.

Dependence/Tolerance: Use of benzodiazepines such as pms-LORAZEPAM, can lead to abuse, misuse, addiction, physical dependence (including tolerance) and withdrawal reactions. Abuse and misuse can result in overdose or death, especially when benzodiazepines are combined with other medicines, such as opioids, alcohol or illicit drugs.
pms-LORAZEPAM should not be administered to individuals prone to drug abuse. Lorazepam may have abuse potential, especially in patients with a history of drug and/or alcohol abuse.
Caution should be observed in patients who are considered to have potential for psychological dependence. It is suggested that the drug should be withdrawn gradually if it has been used in high dosage.
The use of benzodiazepines, including pms-LORAZEPAM, may lead to physical and psychological dependence. The risk of dependence increases with higher doses and longer-term use and is further increased in patients with a history of alcoholism or drug abuse or in patients with significant personality disorders. The dependence potential is reduced when lorazepam is used at the appropriate dose for short-term treatment. In general, benzodiazepines should be prescribed for short periods only (e.g., 2-4 weeks). Continuous long-term use of lorazepam is not recommended.
Discuss the risks of treatment with pms-LORAZEPAM with the patient, considering alternative (including non-drug) treatment options.
Carefully evaluate each patient's risk of abuse, misuse and addiction, considering their medical condition and concomitant drug use, prior to prescribing pms-LORAZEPAM. In individuals prone to substance use disorder, pms-LORAZEPAM should only be administered if deemed medically necessary, employing extreme caution and close supervision.
pms-LORAZEPAM should always be prescribed at the lowest effective dose for the shortest duration possible.
All patients receiving benzodiazepines should be monitored for signs of misuse and abuse. If a substance use disorder is suspected, evaluate the patient and refer them for substance abuse treatment, as appropriate.
Withdrawal: Benzodiazepines, such as pms-LORAZEPAM, can produce withdrawal signs and symptoms, ranging from mild to severe and even life-threatening, following abrupt discontinuation or rapid dose reduction. Other factors that may precipitate withdrawal are switching from a long-acting to a short-acting benzodiazepine, decreasing blood levels of the drug or administration of an antagonist. The risk of withdrawal is higher with higher dosages and/or prolonged use but can occur with short-term use (days to weeks) at recommended therapeutic doses.
The onset of withdrawal signs and symptoms can range from hours to weeks following drug cessation and occur even with tapered dosage. Some symptoms can persist for months. Since symptoms are often similar to those for which the patient is being treated, it may be difficult to distinguish from a relapse of the patient's condition.
Severe or life-threatening signs and symptoms of withdrawal include catatonia, delirium tremens, depression, dissociative effects (e.g., hallucinations), mania, psychosis, seizures (including status epilepticus) and suicidal ideation and behavior.
Other withdrawal signs and symptoms include abdominal cramps, cognitive impairment, diarrhea, dysphoria, extreme anxiety or panic attacks, headache, hypersensitivity to light, noise and physical contact, insomnia, irritability, muscle pain or stiffness, paresthesia, restlessness, sweating, tension, tremors and vomiting. There is also a possibility of rebound anxiety or rebound insomnia.
Abrupt discontinuation should be avoided and treatment - even if only of short duration - should be terminated by gradually tapering the dosage schedule under close monitoring.
Tapering should be tailored to the specific patient. Special attention should be given to patients with a history of seizure.
If a patient experiences withdrawal signs and symptoms, consider postponing the taper or raising the benzodiazepine to the previous dosage prior to proceeding with a gradual taper.
Inform patients of risk of discontinuing abruptly, reducing dosage rapidly or switching medications.
Stress the importance of consulting with their health care professional in order to discontinue safely.
Patients experiencing withdrawal signs and symptoms should seek immediate medical attention. (See Addiction, Abuse and Misuse and Withdrawal under Warnings; Dosing Considerations under Dosage & Administration.)
Immune: 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 dyspnea, 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.
Neurologic: Since pms-LORAZEPAM has a central nervous system depressant effect, patients should be advised against the simultaneous use of other CNS depressant drugs.
Falls and Fractures: There have been reports of falls and fractures among benzodiazepine users due to adverse reactions such as sedation, dizziness and ataxia. The risk is increased in those taking concomitant sedatives (including alcoholic beverages), the geriatric or debilitated patients.
Psychiatric: pms-LORAZEPAM is not recommended for the use in depressive neurosis or in psychotic reactions.
Use in Mental and Emotional Disorders: pms-LORAZEPAM is not recommended for the treatment of psychotic or depressed patients. Since excitement and other paradoxical reactions can result from the use of these drugs in psychotic patients, they should not be used in ambulatory patients suspected of having psychotic tendencies.
As with other anxiolytic-sedative drugs, lorazepam should not be used in patients with non-pathological anxiety. These drugs are also not effective in patients with characterological and personality disorders or those with obsessive-compulsive neurosis.
When using pms-LORAZEPAM, it should be recognized that suicidal tendencies may be present and that protective measures may be required.
Pre-existing depression may emerge or worsen during use of benzodiazepines including lorazepam. The use of benzodiazepines may unmask suicidal tendencies in depressed patients and should not be used without adequate antidepressant therapy.
Renal: Use in Patients with Impaired Renal or Hepatic Function: Since the liver is the most likely site of conjugation of lorazepam and since excretion of conjugated lorazepam (glucuronide) is a renal function, the usual precaution of carefully titrating the dose should be taken, should pms-LORAZEPAM be used in patients with mild to moderate hepatic or renal disease. In patients for whom prolonged therapy with pms-LORAZEPAM is indicated, periodic blood counts and liver function tests should be carried out.
When lorazepam is used in patients with mild to moderate hepatic or renal disease, the lowest effective dose should be considered since drug effect may be prolonged.
Dosage for patients with severe hepatic insufficiency should be adjusted carefully according to patient response. Lower doses may be sufficient in such patients.
As with all benzodiazepines, the use of lorazepam may worsen hepatic encephalopathy; therefore, lorazepam should be used with caution in patients with severe hepatic insufficiency and/or encephalopathy.
Respiratory: pms-LORAZEPAM should be used with caution in patients with compromised respiratory function (e.g., COPD, sleep apnea syndrome).
Concomitant Use with Opioids: Concomitant use of benzodiazepines, including pms-LORAZEPAM, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are not possible (see Risks from Concomitant Use with Opioids under Warnings; Serious Drug Interactions under Interactions).
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with benzodiazepines.
If a decision is made to prescribe pms-LORAZEPAM concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of pms-LORAZEPAM than indicated, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking pms-LORAZEPAM, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation (see Overdosage).
Advise both patients and caregivers about the risk of respiratory depression and sedation when pms-LORAZEPAM is used with opioids.
Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the opioid have been determined.
Driving and Operating Machinery: Excessive sedation has been observed with lorazepam at standard therapeutic doses. Therefore, patients on pms-LORAZEPAM should be warned against engaging in hazardous activities requiring mental alertness and motor coordination, such as operating dangerous machinery or driving motor vehicles.
As is true of other similar CNS-acting drugs, patients receiving lorazepam should not operate machinery or engage in hazardous occupations or drive a motor vehicle for a period of 24 to 48 hours.
Impairment of performance may persist for greater intervals because of extremes of age, concomitant use of other drugs, stress of surgery or the general condition of the patient.
Use in Pregnancy: pms-LORAZEPAM should not be used during pregnancy.
Teratogenic Risk: Several studies have suggested an increased risk of congenital malformations associated with the use of the benzodiazepines during pregnancy (see Pharmacology: Toxicology: Non-clinical Toxicology under Actions).
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, apnea, 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.
Since lorazepam is also a benzodiazepine derivative, its administration is rarely justified in women of child-bearing potential. If the drug is prescribed to a woman of child-bearing potential, she should be warned to contact her physician regarding discontinuation of the drug if she intends to become or suspects that she is pregnant.
In women, blood levels obtained from umbilical cord blood indicate placental transfer of lorazepam and lorazepam glucuronide. pms-LORAZEPAM should not be used during pregnancy. There are insufficient data regarding obstetrical safety of parenteral lorazepam, including use in caesarean section. Such use, therefore, is not recommended.
Use in Lactation: Lorazepam has been detected in human breast milk; therefore, it should not be administered to breast-feeding women, 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).
Use in Children: pms-LORAZEPAM is not intended for use in children under 18 years of age. The safety and effectiveness of pms-LORAZEPAM in children less than 18 years of age has not been established (see Pharmacology: Toxicology: Non-clinical Toxicology under Actions). Because of the lack of sufficient clinical experience, pms-LORAZEPAM is not recommended for use in patients less than 18 years of age.
Paradoxical reactions have been occasionally reported during benzodiazepine use (see Adverse Reactions). Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued.
Use in the Elderly: Elderly and debilitated patients, or those with organic brain syndrome, have been found to be prone to CNS depression after even low doses of benzodiazepines. Therefore, medication should be initiated with very low initial doses in these patients, depending on the response of the patient, in order to avoid over sedation or neurological impairment.
As with any premedicant, extreme care must be used in administering pms-LORAZEPAM to elderly or very ill patients and to those with limited pulmonary reserve, because of the possibility that apnea and/or cardiac arrest may occur.
Clinical trials have shown that patients over the age of 50 years may have a more profound and prolonged sedation with intravenous lorazepam.
For elderly and debilitated patients reduce the initial dose by approximately 50% and adjust the dosage as needed and tolerated.
Long-term use of pms-LORAZEPAM should be avoided in geriatric or debilitated patients who may be more sensitive to benzodiazepines. There is an increased risk of cognitive impairment, delirium, falls, fractures, hospitalizations and motor vehicle accidents in these users. Enhanced monitoring is recommended in this population.

Pregnant Women: pms-LORAZEPAM should not be used during pregnancy.
Breast-feeding: Use in Nursing Mothers: Lorazepam has been detected in human breast milk; therefore, it should not be administered to breast-feeding women, 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).

Adverse Reaction Overview: The adverse reaction most frequently reported was drowsiness.
There is evidence that tolerance develops to the sedative effects of benzodiazepines.
Release of hostility and other paradoxical effects such as irritability and excitability, are known to occur with the use of benzodiazepines. Paradoxical reactions may be more likely to occur in children or the elderly. Should paradoxical reactions occur, use of the drug should be discontinued. In addition, hypotension, mental confusion, slurred speech, over sedation and abnormal liver and kidney function tests and hematocrit values have been reported with these drugs.
Reported adverse reactions (by system) are: Body as a Whole: Angioedema, asthenia, muscle weakness, anaphylactic reactions, change in weight, hypersensitivity reactions, hyponatremia, hypothermia, SIADH.
Cardiovascular: Hypotension, lowering in blood pressure.
Digestive: Nausea, constipation, change in appetite, increase in bilirubin, jaundice, increase in liver transaminases, increase in alkaline phosphatase.
Hematological/Lymphatic: Agranulocytosis, pancytopenia, thrombocytopenia.
Nervous System and Special Senses: Benzodiazepine effects on the CNS are dose-dependent, with more severe CNS depression with higher doses.
Anterograde amnesia, drowsiness, fatigue, sedation, ataxia, confusion, depression, unmasking of depression, dizziness, change in libido, impotence, decreased orgasm, extrapyramidal symptoms, tremor, vertigo, visual disturbances (including diplopia, and blurred vision), dysarthria/slurred speech, headache, convulsions/seizures, amnesia, disinhibition, euphoria, coma, suicidal ideation/attempt, impaired attention/concentration, balance disorder, paradoxical reactions (including anxiety, agitation, excitation, hostility, aggression, rage, sleep disturbances/insomnia, sexual arousal, hallucinations), psychomotor agitation.
Respiratory: The extent of respiratory depression with benzodiazepines is dose-dependent - more severe depression at higher doses.
Respiratory depression, apnea, worsening of sleep apnea, worsening of obstructive pulmonary disease, and ear, nose and throat disturbances.
Skin: Allergic skin reactions, alopecia.
Post-Market Adverse Reactions: Injury, Poisoning and Procedural Complications: There have been reports of falls and fractures in benzodiazepine users due to adverse reactions such as sedation, dizziness and ataxia. The risk is increased in those taking concomitant sedatives (including alcoholic beverages), geriatric and debilitated patients.
Dependence/Withdrawal: Development of physical dependence and withdrawal following discontinuation of therapy has been observed with benzodiazepines such as pms-LORAZEPAM. Severe and life-threatening symptoms have been reported. (See Addiction, Abuse and Misuse under Warnings; Dependence/Tolerance under Precautions.)

Serious Drug Interactions: Concomitant use of pms-LORAZEPAM and opioids may result in profound sedation, respiratory depression, coma and death.
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are not possible.
Limit dosage and durations to the minimum required.
Follow patients for signs and symptoms of respiratory depression and sedation (see Concomitant Use with Opioids under Precautions).
Drug Interactions Overview: If lorazepam is to be used together with other drugs acting on the CNS, careful consideration should be given to the pharmacology of the agents to be employed because of the possible potentiation of drug effects. The benzodiazepines, including pms-LORAZEPAM, produce additive CNS depressant effects when administered with other CNS depressants such as barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, anesthetics and alcohol.
Drug-Behavioural Interactions: Patients should be cautioned not to take alcohol during the administration of lorazepam because of the potentiation of effects that may occur.
pms-LORAZEPAM produces depression of the CNS when administered with ethyl alcohol, phenothiazines, barbiturates, monoamine oxidase (MAO) inhibitors and other antidepressants. When scopolamine is used concomitantly with injectable lorazepam, an increased incidence of sedation, hallucinations and irrational behaviour has been observed.
Drug-Drug Interactions: The drugs listed as follows are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).
Opioids: Due to additive CNS depressant effect, the concomitant use of benzodiazepines, including pms-LORAZEPAM, and opioids increases the risk of profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations of concomitant use of benzodiazepines and opioids to the minimum required. Follow patients closely for respiratory depression and sedation (see Concomitant Use with Opioids under Precautions).
Other Drugs: There have been reports of apnea, coma, bradycardia, heart arrest, and death with the concomitant use of lorazepam injection and haloperidol.
Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, and ataxia.
Concurrent administration of lorazepam with valproate may result in increased plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage should be reduced to approximately 50% when co-administered with valproate.
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 co-administered with probenecid.
Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam.
Drug-Food Interactions: Interactions with food have not been established.
Drug-Herb Interactions: Interactions with herbal products have not been established.
Drug-Laboratory Test Interactions: Interactions with laboratory tests have not been established.

Special Handling Instructions: None.

pms-LORAZEPAM should be stored between 15°C and 30°C, protected from light.

Anxiolytics

N05BA06 - lorazepam ; Belongs to the class of benzodiazepine derivatives anxiolytics. Used in the management of anxiety, agitation or tension.

DD, P₁S₁S₃