C
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phl-LORAZEPAM
(Lorazepam Tablets USP) 0.5, 1 and 2 mg
Pharmel Inc. Date of Preparation: 6111 Royalmount Avenue, Suite #100 July 27, 2007 Montreal, Quebec, Canada H4P 2T4
phl-LORAZEPAM (Lorazepam Tablets USP) 0.5, 1 and 2 mg
Anxiolytic-Sedative
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. Lorazepam has also been shown to possess anti-convulsant activity. Lorazepam is rapidly absorbed after oral administration, with mean peak plasma concentrations of free lorazepam at 2 hours (range between 1-6 hours). 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. The serum half-life of lorazepam ranges between 12 to 15 hours, while that of the conjugate varied between 16 to 20 hours. 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. Anterograde amnesia, a lack of recall of events during period of drug action, has been reported and appears to be dose-related. A bioavailability study comparing two different formulations of lorazepam was performed. Pharmacokinetic and bioavailabilty data of phl-LORAZEPAM were measured from volunteers in the fasting state after a single 4 mg (2 x 2 mg tablets) dose of phl-LORAZEPAM was administered. The results can be summarized as follows:
of pms-LORAZEPAM 2 mg tablet (Pharmascience Inc., Quebec, Canada, Lot #P-0206) versus
ATIVAN 2 mg tablet (Wyeth Ayerst Canada Inc., Canada, Lot #2-WHF-K7) A 4 mg (2 x 2 mg tablets) single oral administration in the fasting state
Measured Data
AUCT (ng.h/mL)
AUC
0-72 h
(ng.h/mL)
C
max
(ng.h/mL)
T
max
611.66 637.69 (31.1) 657.18 686.43 (31.7) 35.26 35.57 (13.3) 577.73 601.05 (29.9) 620.08 645.16 (30.0) 32.52 32.80 (13.7) (102-110) (102-110) _
(h)
1.80 (44.8) 2.40 (48.7)
T1/2el _
(h)
14.84 (22.2) 14.09 (25.0)
For Tmax and T1/2el, the arithmetic mean only is presented
phl-LORAZEPAM (lorazepam) is useful for the short-term relief of manifestations of excessive anxiety in patients with anxiety neurosis. It is also useful as 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.
phl-LORAZEPAM (lorazepam) is contraindicated in patients with myasthenia gravis or acute narrow angle glaucoma, and in those with known hypersensitivity to benzodiazepines.
phl-LORAZEPAM (lorazepam) is not recommended for use in depressive neurosis or in psychotic reactions. Because of the lack of sufficient clinical experience, lorazepam is not recommended for use in patients less than 18 years of age. Since phl-LORAZEPAM has a central nervous system depressant effect, patients should be advised against the simultaneous use of other CNS depressant drugs. Patients should also be cautioned not to take alcohol during the administration of lorazepam because of the potentiation of effects that may occur.
Occupational Hazards:
Excessive sedation has been observed with lorazepam at standard therapeutic doses. Therefore, patients on phl-LORAZEPAM should be warned against engaging in hazardous activities requiring mental alertness and motor coordination, such as operating dangerous machinery or driving motor vehicles.
Use in Pregnancy:
The safety of the use of lorazepam, in pregnancy has not been established. Therefore, phl- LORAZEPAM is not recommended for use during pregnancy or lactation. Several studies have suggested an increased risk of congenital malformations associated with the use of the benzodiazepine chlordiazepoxide and diazepam, and meprobamate, during the first trimester of pregnancy. 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.
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 oversedation or neurological impairment.
Dependence Liability:
phl-LORAZEPAM (lorazepam) should not be administered to individuals prone to drug 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.
Use in Mental and Emotional Disorders:
phl-LORAZEPAM (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 phl-LORAZEPAM, it should be recognized that suicidal tendencies may be present and that protective measures may be required.
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 precautions of carefully titrating the dose should be taken, should phl-LORAZEPAM be used in patients with mild to moderate hepatic or renal disease. In patients for whom prolonged therapy with phl-LORAZEPAM is indicated, periodic blood counts and liver function tests should be carried out.
Drug Interactions:
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 phl-LORAZEPAM, produce CNS depressant effects when administered with such medications as barbiturates or alcohol.
The adverse reaction most frequently reported was drowsiness. Other reported adverse reactions are dizziness, weakness, fatigue and lethargy, disorientation, ataxia, anterograde amnesia, nausea, change in appetite, change in weight, depression, blurred vision and diplopia, psychomotor agitation, sleep disturbance, vomiting, sexual disturbance, headache, skin rashes, gastrointestinal, ear, nose and throat, musculo-skeletaI and respiratory disturbances. Release of hostility and other paradoxical effects, such as irritability and excitability, are known to occur with the use of benzodiazepines. In addition, hypotension, mental confusion, slurred speech, oversedation and abnormal liver and kidney function tests and hematocrit values have been reported with these 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.
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 to 30 mL. Gastric lavage should be instituted as soon as possible and 50 to 100 g of activated charcoal should be introduced to and left in the stomach. 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 dosage of phl-LORAZEPAM (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.
Generalized Anxiety Disorder:
The recommended initial adult daily oral dosage is 2 mg in divided doses of 0.5 mg, 0.5 mg 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.
Drug Substance
Lorazepam
(+-)-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-
benzodiazepin-2-one
H
O
N
OH
Cl N
Cl
Molecular Formula: C15H10Cl2N2O2
321.16
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: 166-168oC pK values: pK1: 13 pK2: 11.5
phl-LORAZEPAM (Lorazepam tablets) contains the label amount of lorazepam as active ingredient and the following non-medicinal ingredients: Lactose, magnesium stearate, microcrystalline cellulose, and polacrilin potassium.
phl-LORAZEPAM should be stored at controlled room temperature (15oC to 30oC), protected from light.
Each white to off-white, flat-face, beveled edge, round tablet, engraved "P" logo on one side and "0.5" on the other side, contains 0.5 mg lorazepam. Supplied in bottles of 100, 500 and 1000 tablets.
Each white to off-white, capsule-shaped, flat-face, beveled edge tablet,
engraved on one side with "P" logo on the left and "1" on the right of the score. 100, Plain on the other side, contains 1 mg lorazepam. Supplied in bottles of 500,1000 and 3000 tablets.
Each white to off-white, oval-shaped flat face, beveled edge tablet, engraved on one side with "P" logo on the left and "" on the right of the score. Plain on the other side, contains 2 mg lorazepam. Supplied in bottles of 100, 500 and 1000 tablets.
Lorazepam is a benzodiazepine with CNS depressant properties. In laboratory animals, it produces disinhibitory, sedative, anticonvulsant, muscle relaxant, ataxic and hypnotic effects. 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 retesting. 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 to 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 to 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 behavior, 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 to 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 behavior 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 dosing of lorazepam in rats diminished rapidly while its anticonflict action remained, findings suggesting that while the anti-anxiety effects of lorazepam endure, any behavior 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 anesthetized 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 anesthetized 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 anesthetized cats and dogs. Dose 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 intravenous injections of lorazepam showed only slight increases in the heart rates of both vehicle control and drug-treated animals. 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. 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. Maximum concentrations of unchanged lorazepam in whole blood and plasma of rats occurred 1/2 to 1 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 6 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. Except for the organs of absorption and excretion, tissue distribution of 14C-lorazepam in rats was nearly uniform. 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 to 6 hours and total recovery in urine and feces over 48 hours was as high as 100% in some species.
Acute Toxicity:
LD50s ranged from 1850-5010 mg/kg in mice to > 5000mg/kg in rats and >2000 mg/kg in dogs. The intraperitoneal LD50s were > 700mg/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.
Long Term Toxicity:
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. Polydypsia 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.
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 3 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.
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Product Monograph pms-Lorazepam, Pharmascience Inc., Date of Preparation, January 22,1987; Date of Revision, March 22, 2001; Control # 066632.