Anxiolytic – Sedative
Action And Clinical Pharmacology: Lorazepam is a benzodiazepine with CNS depressant, anxiolytic and sedative properties. Lorazepam has also been shown to possess anticonvulsant activity. Peak plasma concentrations of free lorazepam after oral administration are reached at 2 hours (range 1 to 6 hours). Peak concentrations are reached in 60 to 90 minutes after i.m. administration and in 60 minutes after sublingual administration. Lorazepam is 85% bound to plasma proteins. Lorazepam is rapidly conjugated to an inactive glucuronide. Very small amounts of other metabolites have also been isolated in man. The serum half-life of lorazepam is approximately 12 to 15 hours while the half-life of the conjugate is 16 to 20 hours. Most of the drug (88%) is excreted in the urine with 75% excreted as the glucuronide.
Anterograde amnesia, decreased or lack of recall of events during period of drug action, has been reported after administration of lorazepam and appears to be dose-related.
Indications And Clinical Uses: The short-term relief of manifestations of excessive anxiety in patients with anxiety neurosis. Adjunct for the relief of excessive anxiety that might be present prior to surgical procedures.
Anxiety and tension associated with the stresses of everyday life usually do not require treatment with anxiolytic drugs.
Injectable lorazepam is useful as an initial anticonvulsant medication for the control of status epilepticus.
Contra-Indications: Myasthenia gravis, acute narrow angle glaucoma, known hypersensitivity to benzodiazepines. Lorazepam injectable is also contraindicated in patients with known hypersensitivity to polyethylene glycol, propylene glycol or benzyl alcohol.
Lorazepam should not be injected intraarterially and care should be taken to prevent its extravasation into tissue adjacent to an artery because of the danger of producing arteriospasm resulting in gangrene which may require amputation.
Manufacturers’ Warnings In Clinical States: 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 lorazepam has a CNS 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 should be warned against engaging in hazardous activities requiring mental alertness and motor coordination, such as operating dangerous machinery or driving motor vehicles.
Prior to i.v. use, lorazepam injection should be diluted with an equal amount of compatible diluent (see Dosage). I.V. injection should be made slowly and with repeated aspiration. Care should be taken to determine that any injection will not be intraarterial and that perivascular extravasation will not take place. Partial airway obstruction may occur in heavily sedated patients. I.V. lorazepam, when given alone in greater than the recommended dose, or at the recommended dose and accompanied by other drugs used during the administration of anesthesia, may produce heavy sedation; therefore, equipment necessary to maintain a patent airway and to support respiration/ventilation should be available.
As with any premedicant, extreme care must be used in administering lorazepam injection 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. Because of the lack of sufficient clinical experience lorazepam injection is not recommended for use in patients less than 18 years of age.
Clinical trials have shown that patients over the age of 50 years may have a more profound and prolonged sedation with i.v. lorazepam. Ordinarily an initial dose of 2 mg may be adequate, unless a greater degree of lack of recall is desired.
There is no evidence to support the use of lorazepam injection in coma, shock or acute alcohol intoxication at this time. When lorazepam injection 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.
As is true of other similar CNS acting drugs, patients receiving injectable 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.
The addition of scopolamine to injectable lorazepam is not recommended, since their combined effect may result in increased incidence of sedation, hallucination and irrational behaviour.
Care should be exercised when administering lorazepam to patients with status epilepticus, especially when the patient has received other CNS depressants or is severely ill. The possibility that respiratory arrest may occur or that the patient may have partial airway obstruction should be considered. Proper resuscitation equipment should be available.
Pregnancy: The safety of the use of lorazepam in pregnancy has not been established. Therefore, it 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 benzodiazepines, 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 childbearing potential. If the drug is prescribed to a woman of childbearing 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. Lorazepam injection should not be used during pregnancy. There are insufficient data regarding obstetrical safety of parenteral lorazepam, including use in cesarean section. Such use, therefore, is not recommended.
Precautions: 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 in these patients with very low initial doses, and increments should be made gradually, depending on the patient’s response, in order to avoid oversedation or neurological impairment. Extreme care must be used in administering lorazepam injection to elderly patients, very ill patients, and to patients with limited pulmonary reserve, because of the possibility that underventilation and/or hypoxic cardiac arrest may occur. Resuscitative equipment for ventilatory support should be readily available.
Dependence Liability: Lorazepam should not be administered to individuals prone to drug abuse.
Observe caution in patients who are considered to have potential for psychological dependence. Lorazepam should be withdrawn gradually if it has been used in high dosage.
As with other benzodiazepines, lorazepam injection has a low potential for abuse and may lead to limited dependence. Although there are no clinical data available for injectable lorazepam in this respect, physicians should be aware that repeated doses over a prolonged period of time may result in limited physical and psychological dependence.
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 nonpathological anxiety. These drugs are also not effective in patients with characterological and personality disorders or those with obsessive-compulsive neurosis.
When using lorazepam, it should be recognized that suicidal tendencies may be present and that protective measures may be required.
Since the liver is the most likely site of conjugation of lorazepam and since excretion of conjugated lorazepam is a renal function, the usual precautions should be taken if lorazepam is used in patients who may have some impairment of renal or hepatic function. In such cases, the dose should be very carefully titrated.
In patients for whom prolonged lorazepam therapy is indicated, periodic blood counts and liver function tests should be carried out.
When injectable 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.
While lorazepam has been shown to control status epilepticus promptly, it is not recommended for maintenance treatment of epilepsy. After seizures are controlled, agents useful in the prevention of further seizures should be administered. In the treatment of status epilepticus due to acute reversible metabolic derangement (e.g., hypoglycemia, hypocalcemia, hyponatremia etc.) immediate efforts should be made to correct the specific defect.
Drug Interactions: If lorazepam is to be combined 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 lorazepam, produce CNS depressant effects when administered with such medications as barbiturates or alcohol.
Lorazepam injection, like other injectable benzodiazepines, also produces depression of the CNS when administered with ethyl alcohol, phenothiazines, barbiturates, MAO inhibitors and other antidepressants. When scopolamine is used concomitantly with injectable lorazepam, an increased incidence of sedation, hallucinations and irrational behavior has been observed.
When lorazepam injection is used i.v. as the premedicant prior to regional or local anesthesia, the possibility of excessive sleepiness or drowsiness may interfere with patient cooperation to determine levels of anesthesia. This is most likely to occur when a dose greater than 0.05 mg/kg is given and when narcotic analgesics are used concomitantly with the recommended dose.
Adverse Reactions: Drowsiness is the most frequently reported adverse effect. Other reported adverse effects 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, musculoskeletal and respiratory disturbances.
Release of hostility and other paradoxical effects, such as irritability and excitability have occurred with 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.
The most frequent adverse effects seen with injectable lorazepam are an extension of the CNS depressant effects of the drug. Excessive sleepiness and drowsiness are the main side effects: the incidences reported depended on the dosage, route of administration, concomitant use of other CNS depressants and the investigators’ expectations concerning the degree and duration of sedation.
When injectable lorazepam was given i.v., patients over 50 years of age had a higher incidence of excessive sedation than patients under 50 years of age. Restlessness, confusion, depression, crying, sobbing, delirium, hallucinations, dizziness, diplopia have been reported. Hypertension and hypotension have occasionally been observed after injectable lorazepam.
Respiratory depression and partial airway obstruction have been observed after injectable lorazepam. Skin rash, nausea and vomiting have been noted occasionally in patients who have received injectable lorazepam combined with other drugs during anesthesia and surgery.
Pain at the injection site, a sensation of burning, and redness in the same area have been reported after i.m. administration of injectable lorazepam. Pain in the immediate postinjection period and redness at the 24 hour observation period also have been reported after i.v. administration of injectable lorazepam.
Symptoms And Treatment Of Overdose: Symptoms: With benzodiazepines, including lorazepam, symptoms of mild overdosage include drowsiness, mental confusion and lethargy. In more serious overdosage, 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 20 to 30 mL of ipecac syrup USP. Institute gastric lavage as soon as possible, and introduce 50 to 100 g of activated charcoal to the stomach and allow it to remain there. Institute general supportive therapy 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 i.v. 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 i.v. 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.
Dosage And Administration: Dosage 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 1 week without reassessment of the need for a limited extension. Initially, not more than 1 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.
The initial daily dose in elderly and debilitated patients 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: Usually 50 µg/kg to a maximum of 4 mg given sublingually (1 to 2 hours before surgery) or i.m. (2 to 3 hours before surgery). As with all premedicant drugs, the dose should be individualized. Doses of other CNS depressant drugs should ordinarily be reduced.
When a rapid onset of action is required, lorazepam may be given i.v., 15 to 20 minutes before surgery. The usual i.v. dose is 44 Âµg/kg or 2.0 mg total, whichever is smaller.
I.V. doses in excess of 2 mg should be restricted to patients of unusual size. A dose of 2 mg should not ordinarily be exceeded in patients over 50 years of age. Doses of other CNS depressants should ordinarily be reduced.
Equipment necessary to maintain a patent airway should be immediately available prior to i.v. administration of lorazepam.
Status Epilepticus: Adults: The usual recommended initial dose of lorazepam is 0.05 mg/kg up to a maximum of 4 mg given by slow i.v. injection. If seizures are terminated, no additional lorazepam is required. If seizures continue or recur after a 10 to 15 minute observation period, an additional i.v. dose of 0.05 mg/kg may be administered. If the second dose does not result in seizure control after another 10 to 15 minute observation period, other measures to control status epilepticus should be employed. A maximum of 8 mg only, of lorazepam, should be administered during a 12 hour period.
Administration: The sublingual tablet, when placed under the tongue, will dissolve in approximately 20 seconds. The patients should not swallow for at least 2 minutes to allow sufficient time for absorption.
When given i.m., lorazepam injection, undiluted, should be injected deep into a muscle mass.
Lorazepam injectable can be used with atropine sulfate, narcotic analgesics, other parenterally used analgesics, commonly used anesthetics and muscle relaxants. The use of scopolamine with lorazepam injection is not recommended since this combination has been associated with a higher incidence of adverse reactions.
Immediately prior to i.v. use, lorazepam injection must be diluted with an equal volume of compatible solution. When properly diluted the drug may be injected directly into the vein or into the tubing of an existing i.v. infusion. The rate of injection should not exceed 2 mg/minute. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if solution is discolored or contains a precipitate.
Lorazepam injection is compatible for dilution purposes with the following solutions: Sterile Water for Injection, USP, Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, Bacteriostatic Sodium Chloride Injection, USP with benzyl alcohol, Bacteriostatic Water for Injection, USP with parabens, Bacteriostatic Water for Injection, USP with benzyl alcohol.
Directions for dilution for i.v. use: Aspirate the desired amount of lorazepam injection into the syringe, then slowly aspirate the desired volume of diluent. Pull back slightly on the plunger to provide additional mixing space. Immediately mix contents thoroughly by gently inverting the syringe repeatedly until a homogenous solution results. Do not shake vigorously since this will result in air entrapment.
Availability And Storage: Injection: Each mL contains: lorazepam 4 mg. Nonmedicinal ingredients: benzyl alcohol, polyethylene glycol and propylene glycol. Single use vials of 1 mL, boxes of 10. Keep refrigerated and protect from light. Do not use if solution is discolored or contains a precipitate. Discard unused portion.
Oral Tablets: 0.5 mg: Each white, round tablet, imprinted 0.5 on one side and W on the other, contains: lorazepam 0.5 mg. Nonmedicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose and polacrilin potassium. Energy: 0.84 kJ (0.20 kcal). Gluten- and tartrazine-free. Bottles of 100, 500 and 1 000.
1 mg: Each white, scored, oblong tablet, imprinted 1 on one side and ATIVAN on the other, contains: lorazepam 1 mg. Nonmedicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose and polacrilin potassium. Energy: 1.63 kJ (0.39 kcal). Gluten- and tartrazine-free. Bottles 100, 1 000 and 2 500.
2 mg: Each white, scored, ovoid tablet, imprinted 2 on one side and ATIVAN on the other, contains: lorazepam 2 mg. Nonmedicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose and polacrilin potassium. Energy: 2.05 kJ (0.49 kcal). Gluten- and tartrazine-free. Bottles of 100, 1 000 and 2 500.
Sublingual Tablets: 0.5 mg: Each pale green, round, flat tablet, imprinted W on one side and 0.5 on the other side contains: lorazepam 0.5 mg. Nonmedicinal ingredients: cornstarch, dye D&C Yellow 10 Aluminum Lake, dye FD&C Blue 1 Aluminum Lake, dye FD&C Yellow 6 Aluminum Lake, lactose, magnesium stearate and microcrystalline cellulose. Energy: 0.59 kJ (0.14 kcal). Gluten- and tartrazine-free. Bottles of 100.
1 mg: Each white, round, flat, tablet, imprinted W on one side and 1 on the other, contains: lorazepam 1 mg. Nonmedicinal ingredients: cornstarch, lactose, magnesium stearate and microcrystalline cellulose. Energy: 0.59 kJ (0.14 kcal). Gluten- and tartrazine-free. Bottles of 100.
2 mg: Each blue, round, flat tablet, imprinted W on one side and 2 on the other, contains: lorazepam 2 mg. Nonmedicinal ingredients: cornstarch, dye FD&C Blue 2 Aluminum Lake, lactose, magnesium stearate and microcrystalline cellulose. Energy: 0.80 kJ (0.19 kcal). Gluten- and tartrazine-free. Bottles of 100. (Shown in Product Recognition Section)
ATIVAN® Wyeth-Ayerst Lorazepam Anxiolytic – Sedative