Data Sheet

NORMISON

Temazepam 10 mg and 20 mg capsules

Description

NORMISON (Temazepam) is a 1,4 benzodiazepine with the chemical name 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1-4-benzodiazepin-2-one. Its structural formula is:

Temazepam is a white, odourless crystalline powder; it is sparingly soluble in alcohol and freely soluble in chloroform, but insoluble in water. The molecular weight is 300.8.

NORMISON is available as soft gelatin capsules.

NORMISON 10 mg capsules also contain macrogol 400, gelatin, anidrisorb 85/70, titanium dioxide, sunset yellow and glycerol.

NORMISON 20 mg capsules also contain macrogol 400, gelatin, sodium ethyl hydroxybenzoate, sodium propyl hydroxybenzoate, titanium dioxide, sunset yellow and glycerol.

Pharmacology

NORMISON hastens the onset of sleep and increases total sleeping time in short term use.

The exact mechanism of action of benzodiazepines has not yet been elucidated; however, benzodiazepines appear to work through several mechanisms. Benzodiazepines presumably exert their effects by binding to specific receptors at several sites within the central nervous system either by potentiating the effects of synaptic or pre-synaptic inhibition mediated by gamma-aminobutyric acid or by directly affecting the action potential generating mechanisms.

Pharmacokinetic studies have shown that NORMISON is well absorbed and has a relatively short elimination half-life of approximately 10 hours (range 5 - 15 hours). Peak plasma levels of the drug occur 35 to 65 minutes after administration of the capsules. , With multiple dosing, steady state is obtained by the third day, and there is little or no accumulation of parent drug or metabolites.

NORMISON is metabolised principally in the liver where most drug is directly conjugated to the glucuronide and excreted in the urine. Some drug is demethylated to oxazepam and eliminated as the glucuronide. The glucuronides of NORMISON have no demonstrable CNS activity. Following a single oral dose, 80% of the dose appears in the urine, mostly as the conjugates, and 12% of the dose appears in the faeces. Less than 2% of the dose is excreted unchanged in the urine. Approximately 96% of unchanged drug is bound to plasma proteins.

Indications

NORMISON is indicated for use as a hypnotic or night-time sedative. As a hypnotic, NORMISON is indicated for severe or disabling insomnia characterised by difficulty in falling asleep, frequent nocturnal awakenings and/or early morning awakening.

NORMISON is indicated for use as a premedicant taken 30-60 minutes prior to surgical or other procedures.

Contraindications

NORMISON is contraindicated in:

1. Patients with a known hypersensitivity to benzodiazepines.
2. Patients with chronic obstructive airways disease with incipient respiratory failure.
3. Patients with sleep apnoea.

Precautions

1. Although hypotension has occurred rarely, NORMISON should be administered with caution to patients in whom a drop in blood pressure might lead to cardiac or cerebral complications. This is particularly important in elderly patients.
2. Transient amnesia or memory impairment has been reported in association with the use of benzodiazepines.
3. NORMISON could increase the muscle weakness in myasthenia gravis and should be used with caution in this condition.
4. Caution should be used in the treatment of patients with acute narrow-angle glaucoma (because of atropine-like side effects).
5. Impaired Renal/Liver Function and Blood Dyscrasias: Patients with impaired renal or hepatic function should use benzodiazepine medication with caution and dosage reduction may be advisable. In rare instances some patients taking benzodiazepines have developed blood dyscrasias, and some have had elevations of liver enzymes. As with other benzodiazepines, periodic blood counts and liver function tests are recommended.
6. Depression, Psychosis and Schizophrenia: NORMISON is not recommended as primary therapy in patients with depression and psychosis. In such conditions, psychiatric assessment and supervision are necessary if benzodiazepines are indicated. Benzodiazepines may increase depression in some patients, and may contribute to deterioration in severely disturbed schizophrenics with confusion and withdrawal. Suicidal tendencies may be present or uncovered and protective measures may be required.
7. Paradoxical reactions such as acute rage, stimulation or excitement may occur; should such reactions occur, NORMISON should be discontinued.
8. Geriatric or debilitated patients: Such patients may be particularly susceptible to the sedative effects of benzodiazepines and associated giddiness, ataxia and confusion, which may increase the possibility of a fall. NORMISON 10 mg is the recommended starting dose for these patients.
9. Impaired Respiratory Function: Caution in the use of NORMISON is recommended in patients with respiratory depression. In patients with chronic obstructive pulmonary disease, benzodiazepines can cause increased arterial carbon dioxide tension and decreased arterial oxygen tension.
10. Epilepsy: Abrupt withdrawal of benzodiazepines in patients with convulsive disorders may be associated with a temporary increase in the frequency and/or severity of seizures.
11. Abuse: Caution must be exercised in administering NORMISON to individuals known to be addiction prone or those whose history suggests they may increase the dosage on their own initiative. It is desirable to limit repeat prescription without adequate medical supervision.
12. Dependence: The use of benzodiazepines may lead to dependence as defined by the presence of a withdrawal syndrome on discontinuation of the drug. Tolerance as defined by a need to increase the dose in order to achieve the same therapeutic effect seldom occurs in patients receiving recommended doses under medical supervision. Tolerance to sedation may occur with benzodiazepines especially in those with drug seeking behaviour. Withdrawal symptoms similar in character to those noted with barbiturates and alcohol have occurred following abrupt discontinuation of benzodiazepines. These symptoms can range from insomnia, anxiety, dysphoria, palpitations, panic attacks, vertigo, myoclonus akinesia, hypersensitivity to light, sound and touch, abnormal body sensations (e.g. feelings of motion, metallic taste), depersonalisation, derealisation, delusional beliefs, hyperreflexia and loss of short term memory, to a major syndrome which may include convulsions, tremor, abdominal and muscle cramps, confusional states, delirium, hallucinations, hyperthermia, psychosis, vomiting and sweating. Such manifestations of withdrawal, especially the more serious ones, are more common in those patients who have received excessive doses over a prolonged period. However, withdrawal symptoms have also been reported following abrupt discontinuation of benzodiazepines taken continuously at therapeutic levels. Accordingly, NORMISON should be terminated by tapering the dose to minimise occurrence of withdrawal symptoms. Patients should be advised to consult with their physician before either increasing the dose or abruptly discontinuing the medication.

Rebound phenomena have been described in the context of benzodiazepine use. Rebound insomnia and anxiety mean an increase in the severity of these symptoms beyond pre-treatment levels following cessation of benzodiazepines. Rebound phenomena in general possibly reflect re-emergence of pre-existing symptoms combined with withdrawal symptoms described earlier. Some patients prescribed benzodiazepines with very short half-lives (in the order of 2 to 4 hours) may experience relatively mild rebound symptoms in between their regular doses. Withdrawal/rebound symptoms may follow high doses taken for relatively short periods.

13. As with all patients taking CNS-depressant medications, patients receiving NORMISON should be warned not to operate dangerous machinery or motor vehicles until it is known that they do not become drowsy or dizzy from NORMISON therapy. Abilities may be impaired on the day following use. In sleep laboratory studies in volunteers, doses of 10 and 20 mg did not significantly affect morning performance, however the 30 mg dose produced impairment of psychomotor behaviour on the morning following night time administration. Patients should be advised that their tolerance for alcohol and other CNS depressants will be diminished and that these medications should either be eliminated or given in reduced dosage in the presence of NORMISON.
14. Following the prolonged use of NORMISON at therapeutic doses withdrawal from the medication should be gradual. An individualised withdrawal timetable needs to be planned for each patient in whom dependence is known or suspected. Periods from four weeks to four months have been suggested. As with other benzodiazepines, when treatment is suddenly withdrawn, a temporary increase of sleep disturbance can occur after use of NORMISON (see Dependence).
15. In general, benzodiazepines should be prescribed for short periods only (e.g. 2-4 weeks). Continuous long-term use of NORMISON is not recommended. There is evidence that tolerance develops to the sedative effects of benzodiazepines. After as little as one week of therapy withdrawal symptoms can appear following the cessation of recommended doses (e.g. rebound insomnia following cessation of a hypnotic benzodiazepine).

Use During Pregnancy

Category C.

Benzodiazepines cross the placenta and may cause hypotonia, reduced respiratory function and hypothermia in the newborn infant. Continuous treatment during pregnancy and administration of high doses in connection with delivery should be avoided. Withdrawal symptoms in newborn infants have been reported with this class of drugs.

The use of benzodiazepines during the first trimester of pregnancy should almost always be avoided. 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.

Non-Teratogenic Effects - The use of benzodiazepines during the last phase of pregnancy or at delivery may require ventilation of the infant at birth.

In animal studies an increased perinatal mortality has been seen following concomitant administration of temazepam and diphenhydramine to rabbits in the later stages of gestation compared with rabbits that received either drug alone. It is recommended that the use of temazepam be avoided in pregnant women receiving antihistamines.

Impairment of Fertility - Fertility in male and female rats was not adversely affected by temazepam.

Use During Lactation

Caution should be exercised when NORMISON is given to breast feeding women.

NORMISON is believed to be excreted in human breast milk and may cause drowsiness and feeding difficulties in the infant.

Paediatric Use

The safety and effectiveness of temazepam has not been established in children less than 16 years of age.

Interactions with Other Drugs

1. The benzodiazepines, including NORMISON, produce additive CNS depressant effects when co-administered with other medications which themselves produce CNS depression, e.g. barbiturates, alcohol, sedatives, tricyclic antidepressants, non selective MAO inhibitors, phenothiazines and other antipsychotics, skeletal muscle relaxants, antihistamines or narcotic analgesics and anaesthetics.
2. The cytochrome P450 system has not been shown to be involved in the disposition of NORMISON and, unlike many benzodiazepines, pharmacokinetic interactions involving the P450 system have not been observed with NORMISON.
3. The anticholinergic effects of other drugs including atropine and similar drugs, antihistamines and antidepressants may be potentiated.
4. Interactions have been reported between some benzodiazepines and anticonvulsants, with changes in the serum concentration of the benzodiazepine or anticonvulsant. It is recommended that patients be observed for altered responses when benzodiazepines and anticonvulsants are prescribed together, and that serum level monitoring of the anticonvulsant be performed more frequently.
5. Minor EEG changes, usually low voltage fast activity, of no known clinical significance, have been reported with benzodiazepine administration.

Effects on Laboratory Tests

No interference with laboratory tests have been identified or reported with the use of temazepam.

Adverse Reactions

All adverse reactions reported with temazepam are common with other benzodiazepine compounds.

More Common Reactions

Nervous System: dizziness, headache, vertigo.

Less Common Reactions

Biochemical: elevated SAP, AST, BUN, bilirubin; proteinuria, neutrophil leucocytosis.

Cardiovascular: palpitation, tachycardia.

Dermatological: macular rash, pruritus.

Gastrointestinal: dry mouth, nausea, vomiting, gastrointestinal upset.

Miscellaneous: loss of taste.

Musculo-Skeletal: leg cramps, weakness.

Nervous System: confusion, disorientation, muzziness, sciatica, tremor, faintness.

Ocular: blurred vision.

Pulmonary: breathlessness.

Psychiatric: depression, irritability, vivid dreams.

Paradoxical reactions such as stimulation, excitement or rage rarely occur (see Precautions).

Dosage and Administration

For use as a hypnotic, the usual adult dose is 20 mg taken one-half hour before retiring. In elderly or debilitated patients, 10 mg NORMISON is the initial recommended dosage.

The recommended dosage range in adults is 10 to 30 mg but dosage should be individualised to the lowest effective dose.

For use as a premedicant, the recommended adult dose is 20-30 mg taken 30-60 minutes prior to surgical or other procedures.

Since insomnia is often transient and intermittent, the prolonged administration of NORMISON is generally not necessary or recommended. In general, hypnotics should be prescribed for short periods only (not more than 2-4 weeks) unless the patient is already reliant on regular hypnotic use. Continuous long term use of NORMISON is not recommended, but intermittent use may be appropriate.

For patients already receiving long-term NORMISON, it is recommended that the need for continued therapy be reviewed periodically.

Overdosage

Overdosage of benzodiazepines is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion and lethargy. In more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, coma, and very rarely proves fatal.

Treatment: In the management of overdosage with any medication, it should be borne in mind that multiple agents may have been taken.

Following overdosage with oral benzodiazepines, vomiting should be induced (within one hour) if the patient is conscious or gastric lavage undertaken with the airways protected if the patient is comatose. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. Hypotension and respiratory depression should be managed according to general principles.

Haemoperfusion and haemodialysis are not useful in benzodiazepine intoxication. The benzodiazepine antagonist flumazenil may be used in hospitalised patients for the reversal of acute benzodiazepine effects. Please consult the flumazenil product information prior to usage.

Presentation

Capsules, 10 mg (soft gelatin, pale orange): 100's HDPE bottles

20 mg (soft gelatin, pale orange, marked WY20): 100's HDPE bottles

Medicine Classification

Controlled Drug C5

Storage

Capsules: Store below 25°C in a cool dry place.

Name and Address

Zuellig Pharma Limited
54 Carbine Road
Mt Wellington
Auckland

Telephone: (09) 570 1080

Date of Preparation:

19 May 2002