INFORMATION FOR HEALTH PROFESSIONALS
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Small, white, capsule-shaped, flat, bevel-edged, compressed tablets of 9mm length and 4mm width. N1 is engraved on one side with a breakline between the N and 1.
LORZEM (lorazepam) is a benzodiazepine which has central nervous system depressant activity. It possesses both anti-anxiety and sedative properties which are useful for the relief of symptoms of anxiety in patients with anxiety neurosis. LORZEM is useful for short term management of symptoms of anxiety that lead to functional disability but is not usually indicated for the treatment of anxiety or tension associated with the stress of everyday life.
Lorazepam is readily and completely absorbed from the gastrointestinal tract after oral absorption. Peak plasma levels are reached at approximately 2 hours. In a comparative bioavailability study after administration of 2mg lorazepam as either Lorzem or Ativan, the following pharmacokinetic results were obtained:
| Parameter | Lorzem | Ativan |
|---|---|---|
| AUC0-∞ (ngh/mL) | 435.31 ± 138.50 | 449.60 ± 144.11 |
| Cmax (ng/mL) | 21.34 ± 3.22 | 22.56 ± 4.21 |
| Tmax (h) | 1.89 ± 0.66 | 1.66 ± 1.06 |
| t½ (h) | 14.65 ± 5.38 | 14.57 ± 5.46 |
| Kel (h-1) | 0.05 ± 0.02 | 0.05 ± 0.02 |
Plasma levels of lorazepam are proportional to dose and there is no evidence of
excessive accumulation after administration. Protein binding of lorazepam within
plasma is approximately 90%. Elimination of lorazepam occurs by metabolism
within the liver and renal excretion of the metabolites.
Glucuronidation to form lorazepam-glucuronide is the major pathway for metabolism. Minor metabolites include a hydroxylated derivative, a quinazolinone derivative and a quinazoline carboxylic acid. Seventy to seventy-five percent of the dose is excreted as the glucuronide in the urine. All the metabolites of lorazepam are inactive. There is no evidence for enzyme induction with lorazepam and it is not a substrate for the N-dealkylating enzymes of cytochrome P450.
The pharmacokinetics of lorazepam is unaltered with advancing age. Studies of lorazepam pharmacokinetics in patients with hepatic disease (hepatitis, alcoholic cirrhosis) indicated there was no change in the absorption, distribution, metabolism or excretion pattern of lorazepam. Renal dysfunction may, however, alter the pharmacokinetics of lorazepam.
LORZEM (lorazepam) is indicated for the short-term relief of symptoms of excessive anxiety in patients with anxiety neurosis. Anxiety and tension associated with the stresses of everyday life usually do not require treatment with anxiolytic drugs.
The dosage of LORZEM (lorazepam) must be individualised 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 weeks supply should be provided and automatic prescription renewals should not be allowed. Subsequent prescriptions, when required, should be limited to short courses of therapy.
Adult Dosage: The recommended initial daily dose for adults is 2mg in divided doses of 0.5, 0.5 and 1.0mg or of 1.0 and 1.0mg. The total daily dose should be carefully decreased or increased by 0.5mg based on the patient's response and tolerance to therapy. The usual daily dosage is 2 to 3mg. Individual patients may have an optimal dosage range of 1 to 4mg daily. A total daily dosage of 6mg should not be exceeded in most cases.
Elderly and Debilitated Patients: These patients should receive initial daily doses of 0.5mg or less. Therapy should be carefully and gradually adjusted, based on response and tolerance to therapy.
LORZEM (lorazepam) is contraindicated in patients with a history of hypersensitivity to benzodiazepines. Patients with myasthenia gravis or with acute narrow angle glaucoma should not receive benzodiazepines.
LORZEM (lorazepam) is not recommended for use in patients with medical depression or psychosis. Dosage has not been established for patients under the age of 18 years. Very young children are usually more sensitive to the CNS depressive effects of benzodiazepines. It is not recommended that other agents with CNS depressant effects be used concomitantly with lorazepam. Alcohol may increase CNS depression due to lorazepam and patients should be cautioned to avoid alcohol while receiving lorazepam.
Usual therapeutic doses of lorazepam have resulted in excessive sedation in some patients. Caution must be advised about participating in hazardous activities or those that require mental alertness and motor co-ordination such as operating dangerous machinery or driving motor vehicles.
The safety of lorazepam in pregnancy has not been established and therefore it is not recommended for use in pregnant or nursing women. An increased risk of congenital malformations has been suggested as due to the use of other benzodiazepines, namely chlordiazepoxide and diazepam, during the initial trimester of pregnancy. Therefore lorazepam, being a benzodiazepine derivative, is rarely justified for use in women of child-bearing age. If a woman of child-bearing age is receiving lorazepam and intends to be or suspects that she is pregnant, she should contact her physician regarding discontinuation of the agent.
Benzodiazepines have been observed to have increased potential for CNS depression in geriatric and debilitated patients.
Because of this potential, therapy should be initiated at a very low dose and then titrated in gradual increments to the response of the patient. This approach may help to avoid oversedation or impairment of neurological functions.
Individuals that are prone to abuse of drugs should not receive LORZEM (lorazepam). Caution should be observed in patients that are perceived to have the potential for psychological dependence. If the agent has been used in high dosage and the decision is made to discontinue therapy, gradual withdrawal is advised.
LORZEM (lorazepam) is not recommended for use in patients with a diagnosis of psychosis or depression.
Excitement and other paradoxical reactions may occur in psychotic patients that are given benzodiazepines. Therefore, these agents should not be given to ambulatory patients that are suspected of having psychotic tendencies. Patients with non-pathological anxiety states should not receive anxiolytic-sedative agents, including lorazepam. These agents are not effective in those patients with character and personality disorders or obsessive-compulsive neurosis.
Patients requiring therapy with lorazepam may have suicidal tendencies present. If this is the case, protective measures may be necessary.
Since lorazepam is conjugated to an inactive metabolite (glucuronide) and excreted in the urine, caution should be observed when LORZEM (lorazepam) is used in patients with some degree of renal or hepatic dysfunction. It is recommended that the dose of lorazepam be titrated carefully to the patients response. Periodic liver function tests and blood counts should be performed when LORZEM (lorazepam) is to be used for extended periods of time.
When other agents that act on the central nervous system are combined in therapy with lorazepam, the medicine effect may be potentiated. Lorazepam may potentiate the CNS effects of alcohol and barbiturates or interfere with the action of narcotics or tricyclic antidepressants.
The most frequently reported adverse effect of lorazepam is drowsiness. Several other adverse experiences have been reported and these include dizziness, weakness, fatigue, confusion, ataxia, amnesia, nausea and vomiting, stomach pain, changes in appetite and weight, depression, blurred vision, agitation, altered sleep patterns, sexual disturbances, headache, skin rash, throat, musculoskeletal and respiratory disturbances.
Paradoxical reactions to benzodiazepines have been known to occur and include irritability, hostility and excitability. These agents have also been associated with hypotension, mental confusion, oversedation, altered liver function tests and haematocrit values.
Lorazepam may produce additive CNS depressant effects if co-administered with other CNS depressants e.g. alcohol, other benzodiazepines. Pharmacokinetic interactions involving the P450 system have not been observed with lorazepam. Lorazepam does not interfere with laboratory tests.
Early manifestations of overdosage include drowsiness and oversedation. Later symptoms may include mental confusion with severe drowsiness, ataxia and progressive loss of consciousness. Large overdoses may result in hypotension and respiratory disturbances and very rarely, death.
For cases where the patient is fully awake and has not vomited spontaneously, syrup of ipecac 20-30ml may be administered to induce vomiting. Gastric lavage should be performed as soon as possible and activated charcoal 50-100g should be administered and left in the stomach. Institute general supportive therapy as necessary, including airway maintenance and i.v. fluids to maintain adequate circulation. Pressor agents, such as noradrenaline or metaraminol may be useful in extreme cases of circulatory insufficiency.
The fatal dose of lorazepam in adults is thought to be as high as 1.85g, however, one six year-old male ingested approximately 30mg and suffered severe central hallucinatory effects that lasted 27 hours.
Store at room temperature protected from light.
Controlled Drug C5.
100 and 500 tablets.
Lorazepam is 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzo-diazepin-2-one. Its molecular formula and weight are C15H10Cl2N2O2 and 321.2 respectively.
Douglas Pharmaceuticals Ltd
P.O. Box 45-027
AUCKLAND 8
Ph: (09) 835-0660
Fax: (09) 835-0665
4 June 1999