Consumer medicine information

RANZEPAM

Diazepam

BRAND INFORMATION

Brand name

Ranzepam

Active ingredient

Diazepam

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using RANZEPAM.

What is in this leaflet

This leaflet answers some common questions about Ranzepam.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

This leaflet was last updated on the date at the end of this leaflet. More recent information may be available. The latest Consumer Medicine Information is available from https://www.ebs.tga.gov.au/ and may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Ranzepam against the benefits it is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with your medicine. You may need to read it again.

What Ranzepam is used for

Diazepam has sedative and muscle relaxant effects and is used to:

  • treat anxiety (anxiety or tension associated with the normal stress of everyday life which usually does not require treatment with medicines)
  • relax muscles
  • treat symptoms such as trembling, confusion and anxiety associated with alcohol withdrawal
  • treat panic attacks

Diazepam belongs to a group of medicines called benzodiazepines.

These medicines are thought to work by their action on brain chemicals.

Benzodiazepines are not recommended as the only treatment of severe mental illnesses and should not be used alone to treat depression.

Your doctor, however, may have prescribed it for another purpose.

Ask your doctor if you have any questions about why diazepam has been prescribed for you.

In general, benzodiazepines such as Ranzepam should be taken for short periods only (around 2 to 4 weeks). Continuous long-term use is not recommended unless advised by your doctor.

The use of benzodiazepines may lead to dependence on the medicine.

This medicine is available only with a doctor's prescription.

Before you take Ranzepam

When you must not take it

Do not take Ranzepam if you have an allergy to:

  • any medicine containing diazepam
  • any of the ingredients listed at the end of this leaflet
  • any other benzodiazepine medicine

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

Do not take this medicine if:

  • you have severe and chronic lung disease
  • you have severe liver disease
  • you have temporary stops in breathing during sleep (sleep apnoea)
  • you suffer from severe muscle weakness known as myasthenia gravis
  • you have drug or alcohol addiction (unless your doctor has prescribed it to help with relieving symptoms of alcohol withdrawal)
  • if the expiry date (EXP) printed on the pack has passed. If you take this medicine after the expiry date has passed, it may not work as well.
  • if the packaging is torn or shows signs of tampering.

If you are not sure whether you should start taking diazepam, talk to your doctor.

Do not give Ranzepam to children less than six months old.

Before you start to take it

Your doctor must know about all the following before you start to take diazepam:

  1. if you are pregnant or plan to become pregnant
    It is not known whether diazepam is harmful to an unborn baby when taken by a pregnant woman. If there is a need to take diazepam when you are pregnant, your doctor will discuss the risks and benefits to you and the unborn baby.
  2. if you are breast-feeding or plan to breast-feed
    Diazepam may pass into the breast milk and cause drowsiness and/or feeding difficulties in the baby. Ranzepam is not recommended for use while breast-feeding.
  3. if you have any other health problems including:
    - liver, kidney or lung disease
    - high or low blood pressure
    - glaucoma (high pressure in the eye)
    - depression, schizophrenia or other mental illness
    - epilepsy (fits or convulsions)
    - history of alcohol and drug abuse
  4. if you drink alcohol
    Alcohol may increase the effects of diazepam.
  5. if you are allergic to any other medicines, foods, dyes or preservatives
  6. if you are intolerant of, or allergic to lactose. Ranzepam contains lactose.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may interfere with Ranzepam. These medicines include:

  • other sleeping tablets, sedatives or tranquillisers
  • medicines used to treat depression
  • medicines to control fits
  • medicines for allergies or colds (e.g. antihistamines)
  • pain relievers
  • muscle relaxants
  • cimetidine and omeprazole (medicines used to treat ulcers)
  • disulfiram (a medicine used in the treatment of alcoholism)
  • cisapride (a medicine used to treat gastric reflex)
  • ketoconazole (a medicine used to treat fungal infections).

These medicines may be affected by diazepam or may affect how well it works. Your doctor or pharmacist can tell you what to do if you are taking any of these medicines. They also have a more complete list of medicines to be careful with or avoid while taking Ranzepam.

If you are taking any other medications, check with your doctor before you start to take Ranzepam.

How to take Ranzepam

How much to take

Take Ranzepam exactly as your doctor has prescribed. Your doctor will tell you how many Ranzepam tablets to take each day.

The dose of diazepam varies from person to person depending on age and the condition being treated. The usual adult dose is between 5 and 40 mg daily. Children, elderly and very ill patients may need to take less.

How to take it

Swallow Ranzepam tablets with a full glass of water.

When to take it

Diazepam can be taken up to three times a day. Your doctor will tell you how much you need to take. The tablets can be taken with or without food.

How long to take it

Usually, diazepam should be taken for short periods only (for example, for 2 to 4 weeks). Continuous long-term use is not recommended unless advised by your doctor. The use of benzodiazepines may lead to dependence on the medicine.

Continue taking Ranzepam until your doctor tells you to stop.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too much diazepam.

Do this even if there are no signs of discomfort or poisoning.

Also report any other medicine or alcohol which has been taken.

You may need urgent medical attention.

If you have taken too much diazepam, you may feel drowsy, confused, dizzy, have difficulty breathing, feel weak or become unconscious. It is important that you recognise these signs of overdose early.

If you are not sure what to do, contact your doctor or pharmacist.

While you are taking Ranzepam

Things you must do

Tell all doctors, dentists and pharmacists who are treating you that you are taking diazepam.

Do not take any other medicines whether they require a prescription or not without first telling your doctor.

If you become pregnant while you are taking Ranzepam, tell your doctor immediately.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise your doctor may think that it was not effective and change your treatment unnecessarily.

Tell your doctor if you feel the tablets are not helping your condition.

Be sure to keep all of your appointments with your doctor so that your progress can be checked.

Always discuss with your doctor any problems or difficulties during or after taking Ranzepam.

Things you must not do

Do not drive or operate machinery until you know how diazepam affects you. Diazepam may cause drowsiness or dizziness in some people and therefore may affect alertness. Make sure you know how you react to diazepam before you drive a car or operate machinery or do anything else that could be dangerous if you are drowsy, dizzy or not alert. Even if you take this medicine at night, you may still be drowsy or dizzy the next day.

Do not take diazepam for a longer time than your doctor has prescribed. Diazepam should be taken for short periods only (for example, 2 to 4 weeks), unless advised by your doctor.

Do not stop taking your medicine or lower the dose, without first checking with your doctor. Stopping this medicine suddenly may cause some unwanted effects. Your doctor may decide to slowly reduce your dose of diazepam before you can stop taking it completely.

Do not let yourself run out of medicine on weekends or holidays.

Do not suddenly stop taking diazepam if you suffer from epilepsy. Stopping this medicine suddenly may make your epilepsy worse.

Do not take Ranzepam to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful if you are elderly, unwell, drinking alcoholor taking other medicines. Your doctor may suggest that you avoid alcohol or reduce the amount of alcohol you drink while you are taking Ranzepam.

Some people may experience side effects such as drowsiness, confusion, dizziness and unsteadiness, which may increase the risk of a fall.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Ranzepam. This medicine helps most people with anxiety but it may have unwanted side effects in a few people. All medicines may have side effects. Sometimes they are serious, most of the time they are not. Some side effects may require medical treatment.

If you are elderly, unwell or taking other medicines, you may have an increased chance of getting side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • drowsiness, tiredness
  • dizziness, unsteadiness
  • loss of memory, inattentiveness, confusion, lack of concentration
  • headache, hangover feeling in the morning
  • slurred speech
  • unpleasant dreams

The above list includes the more common side effects of diazepam. They are usually mild and may disappear if the dose is reduced.

Tell your doctor immediately or go to casualty at your nearest hospital if you notice any of the following:

  • sudden anxiety or excitation
  • restlessness, agitation, irritability, anger, abnormal behaviour
  • hallucinations or delusions
  • severe sleep disturbances
  • difficulties in breathing or choking or coughing

These are serious side effects. You may need medical attention. Serious side effects are rare.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor or pharmacist if you do not understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using Ranzepam

Storage

Keep your tablets in the original packaging until it is time to take them. If you take the tablets out of the blister pack, they may not keep well.

Keep Ranzepam in a cool dry place, protected from light and where the temperature stays below 25°C.

Do not store diazepam, or any other medicines in a bathroom or near a sink.

Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep Ranzepam where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking diazepam or the medicine has passed the expiry date, ask your pharmacist what to do with any tablets that are left over.

Where to go for further information

Pharmaceutical companies are not in a position to give people an individual diagnosis or medical advice. Your doctor or pharmacist is the best person to give you advice on the treatment of your condition.

Product description

What Ranzepam looks like

  • Ranzepam 2 mg tablets: white to off-white round, biconvex uncoated tablets debossed with ‘2’ on one side and plain on the other side; available in blister packs of 50 tablets.
  • Ranzepam 5 mg tablets: white to off-white round, flat bevelled edged uncoated tablets debossed with ‘5’ and a scoreline on one side and plain on the other side; available in blister packs of 50 tablets.

Ingredients

Ranzepam tablets contain 2 mg or 5 mg of diazepam as the active ingredient.

They also contain the following inactive ingredients:

  • lactose
  • maize starch
  • silica - colloidal anhydrous
  • magnesium stearate
  • purified talc.

This medicine does not contain gluten, sucrose, tartrazine or any other azo dyes.

Sponsor

Ranbaxy Australia Pty Ltd
9-13 Waterloo Road
Macquarie Park NSW 2113
Australia

Australian Registration Numbers

  • Ranzepam 2 mg tablets: AUST R 134589.
  • Ranzepam 5 mg tablets: AUST R 134473.

This leaflet was prepared in March 2014.

Published by MIMS September 2014

BRAND INFORMATION

Brand name

Ranzepam

Active ingredient

Diazepam

Schedule

S4

 

Name of the medicine

Diazepam.

Excipients.

Lactose monohydrate, maize starch, anhydrous colloidal silica, magnesium stearate and purified talc.

Description

Chemical name: 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one. Molecular formula: C16H13ClN2O. MW: 284.74. CAS: 439-14-5. Diazepam is a white or almost white crystalline powder, very slightly soluble in water, soluble in ethanol (96%).

Pharmacology

Pharmacodynamics.

Diazepam is a member of the group of classical benzodiazepines and exhibits anxiolytic, sedative, muscle relaxant and anticonvulsant effects. This is presumed to be the result of facilitating the action in the brain of gamma-aminobutyric acid, a naturally occurring inhibitory transmitter.

Pharmacokinetics.

Absorption.

Diazepam is rapidly and completely absorbed from the gastrointestinal tract, peak plasma concentrations appearing 30-90 minutes after oral intake. The speed of onset after intramuscular administration (IM) is variable, depending on the muscle mass used and other factors.

Distribution.

Diazepam is 98% protein bound in the plasma, and is excreted mainly (about 70%) in the urine in free form or (predominantly) as conjugated metabolites. Diazepam and its metabolites cross the blood brain and placental barriers and are also found in breast milk.

Metabolism.

Diazepam is metabolised to a hydroxyl-diazepam (temazepam) and nordiazepam (t1/2 approximately 96 hours) and ultimately to oxazepam.
The oxidative metabolism of diazepam is mediated by CYP3A and CYP2C19 isoenzymes. Oxazepam and temazepam are further conjugated to with glucuronic acid.

Elimination.

The plasma concentration time curve of diazepam is biphasic, an initial rapid and extensive distribution phase with a half-life of up to 3 hours, followed by a prolonged terminal elimination phase (half-life 20 to 48 hours). The elimination half-life is 90 hours at age 80 and increased two to threefold in patients with cirrhosis.
Pharmacokinetics in special populations. The elimination half-life may be prolonged in the newborn, the elderly and patients with hepatic or renal disease and it should be noted that the plasma concentration may take correspondingly longer to reach steady state.

Indications

Diazepam is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.
In acute alcohol withdrawal, diazepam may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis.
Diazepam is a useful adjunct for the relief of reflex muscle spasm due to local trauma (injury, inflammation) to muscles, bones and joints. It can also be used to combat spasticity due to upper motor neuron lesions such as cerebral palsy and paraplegia, as well as in athetosis and stiff man syndrome.

Contraindications

Diazepam is contraindicated in patients with:
known hypersensitivity to benzodiazepines;
chronic obstructive pulmonary disease with incipient respiratory failure.
Oral diazepam is also contraindicated in patients with:
severe respiratory insufficiency;
severe hepatic insufficiency;
sleep apnoea syndrome;
myasthenia gravis;
dependence on CNS depressants including alcohol. An exception to the latter is the management of acute withdrawal reactions.
Benzodiazepines are not recommended for the primary treatment of psychotic illness.
Benzodiazepines should not be used alone to treat depression or anxiety associated with depression as suicide may occur in such patients.

Precautions

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 diazepam. Such concomitant use has the potential to increase the clinical effects of diazepam, possibly including severe sedation, clinically relevant respiratory and/or cardiovascular depression (see Interactions with Other Medicines).
In general, benzodiazepines should be prescribed for short periods only (e.g. 2-4 weeks). Continuous long-term use of diazepam 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 benzodiapine).
Following the prolonged use of diazepam 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 in sleep disturbance can occur after use of diazepam (see Precautions, Dependence).
Since Ranzepam contains lactose, patients with rare hereditary problems of galactose intolerance (the Lapp lactase deficiency or glucose/ galactose malabsorption) should not take this medicine.

Hypotension.

Although hypotension has occurred rarely, diazepam 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.

Amnesia.

Transient amnesia or memory impairment has been reported in association with the use of benzodiazepines. Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behavior.

Acute narrow angle glaucoma.

Caution should be used in the treatment of patients with acute narrow angle glaucoma (because of atropine-like side effects).

Use in pregnancy.

(Category C)
The safety of diazepam for use in human pregnancy has not been established. Diazepam and its metabolites readily cross the placenta. An increased risk of congenital malformation associated with the use of benzodiazepines during the first trimester of pregnancy has been suggested. Benzodiazepines should be avoided during pregnancy unless there is no safer alternative. Benzodiazepines cross the placenta and may cause hypotension, 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. Special care must be taken when diazepam is used during labour and delivery, as single high doses may produce irregularities in the foetal heart rate and hypotonia, poor sucking, hypothermia and moderate respiratory depression (floppy infant syndrome) in the neonate. With newborn infants it must be remembered that the enzyme system involved in the breakdown of the drug is not yet fully developed (especially in premature infants).

Use in lactation.

Diazepam is excreted in human breast milk and may cause drowsiness and feeding difficulties in the infant. Breastfeeding is not recommended in patients receiving diazepam.

Use in children.

Efficacy and safety of diazepam has not been established in the neonate (30 days or less in age). Prolonged central nervous system depression has been observed in neonates due to inability to transform the drug. In view of lack of adequate clinical experience chronic oral use is not recommended in children younger than 6 months.

Use in elderly.

There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly. Elderly or debilitated patients may be particularly susceptible to the sedative effects of benzodiazepines and associated giddiness, ataxia and confusion, which may increase the risk of a fall.
Lower doses should be used for elderly and debilitated patients.

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 elevation of liver enzymes. As with other benzodiazepines, periodic blood counts and liver function tests are recommended.

Depression, psychosis and schizophrenia.

Diazepam is not recommended as primary therapy in patients with depression and/or 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.

Paradoxical reactions.

Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, delusion, nightmares, hallucinations, psychoses, inappropriate behavior and other adverse behavioural effects, acute rage, stimulation or excitement may occur. Should such reactions occur, diazepam should be discontinued. They are more likely to occur in children and in the elderly.

Carcinogenicity.

The carcinogenicity potential of oral diazepam has been studied in several rodent species. An increase in the incidence of malignant hepatocellular tumours occurred in male rats and mice following lifetime dietary administration of diazepam. This was not observed in female rats and mice.

Genotoxicity.

Limited data from a number of studies have provided weak evidence of a genotoxic potential.

Impaired respiratory function.

Caution in the use of diazepam is recommended in patients with respiratory depression. In patients with chronic obstructive pulmonary disease, benzodiazepines can cause increased arterial carbon dioxide tension and decreased oxygen tension. A lower dose is recommended for patients with chronic respiratory insufficiency, due to the risk of respiratory depression.

Epilepsy.

When diazepam is administered to persons with convulsive disorders, an increase in the frequency and/or severity of grand mal seizures may occur, necessitating increased anticonvulsant medication. Abrupt withdrawal of benzodiazepines in persons with convulsive disorders may be associated with a temporary increase in the frequency and/or severity of seizures.

Abuse.

Extreme caution must be exercised in administering diazepam to individuals with a history of alcohol or drug abuse, dependence on CNS depressants, those 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.

Dependence.

The use of benzodiazepines and benzodiazepine-like agents may lead to the development of physical and psychic dependence (see Adverse Effects), as defined by the presence of a withdrawal syndrome on discontinuation of the drug. The risk of dependence increases with dose and duration of treatment. It is more pronounced in patients on long-term therapy and/or high dosage and particularly so in predisposed patients with a history of alcohol or drug abuse. 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 once physical dependence to benzodiazepines has developed or following abrupt discontinuation of benzodiazepines. These symptoms range from insomnia, anxiety, dysphoria, palpitations, panic attacks, vertigo, myoclonus, akinesia, hypersensitivity to light, sound and touch, abnormal body sensations (e.g. feeling of motion, metallic taste), depersonalisation, derealisation, delusional beliefs, hyper-reflexia and loss of short term memory, to a major syndrome which may include convulsions, tremor, abdominal and muscle cramps, confusional state, delirium, hallucinations, hyperthermia, psychosis, vomiting and sweating. Such manifestations of withdrawal, especially the more serious ones, are more common in patients who have received excessive doses over a prolonged period.
However, withdrawal symptoms have been reported following abrupt discontinuation of benzodiazepines taken continuously at therapeutic levels. Accordingly, diazepam 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 pretreatment 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 order of 2 to 4 hours) may experience relatively mild rebound symptoms in between their regular doses. Withdrawal/ rebound symptoms may follow high doses for relatively short periods.

Ability to drive and use machines.

Sedation, amnesia, impaired concentration and impaired muscle function may adversely affect the ability to drive or operate machinery. As with all patients taking CNS depressant medications, patients receiving diazepam should be warned not to operate dangerous machinery or motor vehicles until it is known that they do not become drowsy or dizzy from diazepam therapy. Abilities may be impaired on the day following use.

Interactions

Enhanced effects on sedation, respiratory depression (including apnoea) and haemodynamic instability may occur when diazepam is coadministered with any centrally acting depressants, which themselves produce CNS depression (e.g. barbiturates, alcohol, anxiolytics, sedatives, antidepressants including tricyclic antidepressants and nonselective MAO inhibitors, hypnotics, antiepileptic drugs, phenothiazines and other antipsychotics, skeletal muscle relaxants, antihistamines, narcotic analgesics and anaesthetics.
Alcohol should be avoided in patients receiving diazepam (see Precautions).
Concomitant use with alcohol is not recommended due to enhancement of the sedative effect.
The oxidative metabolism of diazepam, leading to the formation of nordiazepam and temazepam, is mediated predominantly by the CYP2C19 and CYP3A cytochrome P450 isoenzymes, respectively. Consequently, substrates which are modulators of CYP3A or CYP2C19, may potentially alter the pharmacokinetics of diazepam. Nordiazepam and temazepam are further metabolised to oxazepam.
Diazepam may interact with disulfiram, cimetidine, ketoconazole, fluvoxamine, fluoxetine, diltiazem or omeprazole resulting in increased plasma levels of diazepam. Patients should be observed closely for evidence of enhanced benzodiazepine response (e.g. increased and prolonged sedation) during concomitant treatment with either disulfiram or cimetidine; some patients may require a reduction in benzodiazepine dosage.
There have also been reports that the metabolic elimination of phenytoin is affected by diazepam. Cisapride may lead to a temporary increase in the sedative effects of orally administered benzodiazepines due to faster absorption.
The anticholinergic effects of other drugs including atropine and similar drugs, antihistamines and antidepressants may be potentiated.
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 is performed more frequently.
See Overdosage for warnings about other central nervous system depressants, including alcohol.

Effects on laboratory tests.

Minor EEG changes, usually low voltage fast activity, of no known clinical significance have been reported with benzodiazepine administration.
Diazepam can inhibit binding of thyroxine and liothyronine to their binding proteins resulting in erroneously abnormal values from thyroid function test.

Adverse Effects

Most commonly reported undesirable effects are fatigue, drowsiness, muscle weakness and ataxia; they are usually dose related.
Isolated instance of neutropenia have been seen.
Dizziness has been reported occasionally with oral diazepam.
Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher doses. Amnestic effects may be associated with inappropriate behaviour.

Nervous system disorders.

Amnesia, fatigue, drowsiness, muscle weakness, ataxia, dysarthria, slurred speech, headache, tremor, dizziness.

Psychiatric disorders.

Paradoxical reactions such as restlessness, acute hyperexcitation, agitation, irritability, anxiety, increased muscle spasticity, insomnia, sleep disturbances, nightmares, hallucinations, aggression, delusion, anger, psychoses, abnormal behaviour, stimulation and other adverse behavioural effects are known to occur when using benzodiazepines. Should these occur, use of the drug should be discontinued. They are more likely to occur in children and in the elderly.
Confusion, emotional poverty, alertness decreased, depression, libido increased or decreased.
Chronic use (even at therapeutic doses) of oral diazepam may lead to the development of physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena (see Precautions, Dependence).
Abuse of benzodiazepines has been reported (see Precautions, Dependence).

Injury, poisoning and procedural complications.

There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.

Gastrointestinal disorders.

Nausea, dry mouth or hypersalivation, constipation and other gastrointestinal disturbances.

Eye disorders.

Diplopia, vision blurred.

Vascular disorders.

Hypotension, circulatory depression.

Investigations.

Irregular heart rate, very rarely increased transaminases, increased blood alkaline phosphatase.

Renal and urinary disorders.

Incontinence, urinary retention.

Skin and subcutaneous tissue disorders.

Skin reactions, such as rash.

Ear and labyrinth disorders.

Vertigo.

Cardiac disorders.

Cardiac failure including cardiac arrest.

Respiratory disorders.

Respiratory depression including respiratory failure.

Hepatobiliary disorders.

Very rarely jaundice.

Haemopoietic disorders.

Isolated instances of neutropenia.

Dosage and Administration

Oral.

For maximal beneficial effect, the dosage should be carefully individualised. Dosage may need to be reduced in patients with hepatic or renal disease as the elimination half-life may be prolonged in this subgroup.
Elderly patients should be given a reduced dose. These patients should be checked regularly at the start of treatment in order to minimise the dosage and/or frequency of administration to prevent overdose due to accumulation.

Usual adult dosage.

5-40 mg daily.

Average dosage for ambulatory patients.

2 mg three times daily or 5 mg in the evening and 2 mg once or twice during the day.

Elderly or debilitated patients.

2 mg twice daily or half the usual adult dose.

Children, 6 months to 3 years.

1-6 mg daily.

Children, 4 to 14 years.

4-12 mg daily or calculated from 0.1-0.3 mg/kg bodyweight.

Hospital treatment of tension, excitation, motor unrest.

10 to 15 mg three times daily until the acute symptoms subside.

Muscle spasm.

10-30 mg daily.
Benzodiazepines should not be given to children without careful assessment of the indication; the duration of treatment must be kept to a minimum.

Overdosage

Symptoms.

Overdosage of benzodiazepines is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, disarthria, nystagmus, mental confusion and lethargy. In more serious cases, symptoms may include ataxia, areflexia, hypotonia, hypotension, apnoea, cardiorespiratory depression, coma and very rarely death. Coma, may be more protracted and cyclical, particularly in elderly patients. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease.
Benzodiazepines increase the effects of other central nervous system depressants, including alcohol. When combined with other CNS depressants, the effects of overdosage are likely to be severe and may prove fatal.

Treatment.

Treatment of overdose is symptomatic; institute supportive measures as indicated by the patient's clinical state. If the overdosage is known to be small, observation of the patient and monitoring of their vital signs only may be appropriate. In adults or children who may have taken an overdose of benzodiazepines within 1-2 hours, consider activated charcoal with airway protection if indicated.
If CNS depression is severe, consider the use of flumazenil (Anexate), a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered with flumazenil will require monitoring after its effects have worn off. Flumazenil may precipitate seizures and is to be used with extreme caution in the presence of drugs that reduce seizures threshold (e.g. tricyclic antidepressants) and epileptic patients who have been treated with benzodiazepines. Refer to prescribing information for flumazenil (Anexate), for further information on the correct use of this drug.
Haemoperfusion and haemodialysis are not useful in benzodiazepine intoxication.
Contact the Poisons Information Centre on 131 126 (Australia) for advice on the management of overdosage.

Presentation

Tablets (white to off white, round, uncoated, plain on reverse), 2 mg (biconvex, marked 2 on one side), 5 mg (flat, bevelled edged, scored, marked 5 on one side): 50's (PVC/PVdC/Al blister pack).

Storage

Store below 25°C. Protect from light.

Poison Schedule

S4.