Consumer medicine information

DBL Diazepam Injection

Diazepam

BRAND INFORMATION

Brand name

DBL Diazepam Injection

Active ingredient

Diazepam

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using DBL Diazepam Injection.

SUMMARY CMI

DBL™ Diazepam Injection

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I being treated with DBL Diazepam Injection?

DBL Diazepam Injection contains the active ingredient diazepam. DBL Diazepam Injection is used for a number of conditions including: tension and anxiety, repeated or prolonged epileptic seizures, to help relax you before an operation, muscle spasm, for the relief of symptoms of alcohol withdrawal, and muscle stiffness due to cerebral palsy or paraplegia.

For more information, see Section 1. Why am I being treated with DBL Diazepam Injection? in the full CMI.

2. What should I know before treatment with DBL Diazepam Injection?

Do not start treatment if you have ever had an allergic reaction to DBL Diazepam Injection, or any medicine in the benzodiazepine group, or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before treatment with DBL Diazepam Injection? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with DBL Diazepam Injection and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How is DBL Diazepam Injection given?

Your doctor will decide how much DBL Diazepam Injection you will receive. This depends on your condition. DBL Diazepam Injection should only be given by a doctor, nurse, or other trained person.

More instructions can be found in Section 4. How is DBL Diazepam Injection given? in the full CMI.

5. What should I know during treatment with DBL Diazepam Injection?

Things you should do
  • Remind any doctor, nurse, dentist, or pharmacist who is treating you that you are using DBL Diazepam Injection.
Things you should not do
  • Do not stop treatment with this medicine suddenly without speaking to your doctor. Your doctor may want to gradually reduce the amount of diazepam you have been receiving, before stopping it completely.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how DBL Diazepam Injection affects you.
  • Diazepam may cause dizziness, lightheadedness, drowsiness and disorientation in some people.
Drinking alcohol
  • Do not drink alcohol while you are given diazepam.
  • If you drink alcohol, dizziness and/or drowsiness may be worse.

For more information, see Section 5. What should I know during treatment with DBL Diazepam Injection? in the full CMI.

6. Are there any side effects?

Common side effects include: fatigue, drowsiness, lack of coordination, dizziness, headache, light headedness, fainting, loss of memory, inattentiveness, confusion, lack of concentration, skin problems, depressed mood, dryness of the mouth, double vision, difficulty speaking/slurred speech, fever, pain, swelling and redness at the injection site, palpitations (irregular heart beat), muscle problems, difficulty urinating, stomach problems, unpleasant dreams.

Serious side effects include: breathing difficulties, choking or coughing, fast breathing, fast or irregular heart beat, allergic reaction symptoms, sudden anxiety or excitation, behavioural problems, restlessness, agitation, irritability, hallucinations or delusions, abnormal behaviour, severe sleep disturbances, unusual bleeding or bruising, yellowing of the skin or eyes.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

DBL™ Diazepam Injection

Active ingredient(s): diazepam (dye-AZ-eh-pam)

Consumer Medicine Information (CMI)

This leaflet provides important information about using DBL Diazepam Injection. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using DBL Diazepam Injection.

Where to find information in this leaflet:

1. Why am I being treated with DBL Diazepam Injection?
2. What should I know before treatment with DBL Diazepam Injection?
3. What if I am taking other medicines?
4. How is DBL Diazepam Injection given?
5. What should I know during treatment with DBL Diazepam Injection?
6. Are there any side effects?
7. Product details

1. Why am I being treated with DBL Diazepam Injection?

DBL Diazepam Injection contains the active ingredient diazepam. DBL Diazepam Injection belongs to a group of medicines known as benzodiazepines (ben-zo-dye-AZ-eh-peens). These medicines appear to have their effect by acting on certain areas of the brain.

Diazepam has sedative and muscle relaxant effects.

DBL Diazepam Injection is used for a number of conditions, including:

  • tension and anxiety
  • repeated or prolonged epileptic seizures (convulsions/fits)
  • to help relax you before an operation (preoperative medication)
  • muscle spasm
  • for the relief of symptoms of alcohol withdrawal
  • muscle stiffness due to cerebral palsy or paraplegia.

Your doctor may have prescribed diazepam for another reason. Ask your doctor if you have any questions about why DBL Diazepam Injection has been prescribed for you.

In general, medicines such as DBL Diazepam Injection should be used for short periods only (for example 2 - 4 weeks). Continuous long term use is not recommended unless advised by your doctor. The use of this medicine may lead to dependence on diazepam.

This means you may experience unpleasant feelings if you stop using this medicine suddenly. However, it is also important to treat your condition. Your doctor will be able to advise you on how to prevent and manage this.

2. What should I know before treatment with DBL Diazepam Injection?

Warnings

You must not be given DBL Diazepam Injection if:

  • you are allergic to diazepam, or any other medicine in the benzodiazepine group, or any of the ingredients listed at the end of this leaflet.
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.
Always check the ingredients to make sure you can use this medicine.
  • you have a breathing disorder, known as severe or chronic obstructive airways disease, or with respiratory failure.
  • you have depression, psychosis or schizophrenia that is not being treated.
  • you have myasthenia gravis, a condition in which the muscles become weak and tire easily.
  • you are in a medical shock, coma, or have poor heart and lung function or alcohol intoxication.
  • the expiry date (EXP) printed on the pack has passed.
If you are given this medicine after the expiry date has passed, it may not work as well.
  • the packaging is torn or shows signs of tampering.

If you are not sure whether you should be given diazepam talk to your doctor or pharmacist.

Check with your doctor if you:

  • have any allergies to:
    - any other medicines
    - any other substances, such as foods, preservatives or dyes.
  • have or have had any other medical conditions, especially the following:
    - glaucoma
    - lung, kidney or liver problems
    - depressed mood or other mental illness such as schizophrenia
    - previous drug or alcohol addiction problems
    - high or low blood pressure
    - fits or convulsions (epilepsy).
  • take any medicines for any other condition.

If you have not told your doctor or pharmacist about any of the above, tell them before you are given DBL Diazepam Injection.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Your doctor will discuss the risks and benefits of you being given diazepam during pregnancy.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

DBL Diazepam Injection may pass into the breast milk and cause drowsiness and/or feeding difficulties in the baby.

It is not recommended for use while breastfeeding.

3. What if I am taking other medicines?

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

Some medicines and DBL Diazepam Injection may interfere with each other and affect how they work. These include:

  • disulfiram, a medicine used to treat alcohol dependency
  • levodopa, a medicine used in the management of Parkinson's disease
  • isoniazid, rifampicin, clarithromycin or erythromycin, medicines used to treat some bacterial infections
  • ketoconazole or fluconazole, medicines used to treat fungal infections
  • ritonavir, a medicine used to treat HIV/AIDS
  • some medicines used to treat depression (e.g. amitriptyline, fluoxetine, fluvoxamine)
  • some medicines used to reduce stomach acid or treat stomach ulcers such as esomeprazole, cimetidine and omeprazole
  • anticholinergics (e.g. atropine) which may be taken for stomach cramps
  • some medicines used to treat anxiety, mental illness with disordered thinking (e.g. clozapine, remoxipride, olanzapine)
  • some medicines for epilepsy/fitting (e.g. sodium valproate, phenytoin, carbamazepine)
  • antihistamines
  • strong pain relievers or opioids (e.g. ketamine, methadone, morphine, fentanyl, oxycodone or codeine)
  • alcohol
  • sedatives and sleeping tablets
  • other medicines which may make you feel drowsy
  • muscle relaxants and anaesthetics
  • combined oral contraceptives
  • diltiazem, verapamil, medicines used to treat heart disease
  • idelalisib, a medicine used to treat blood cancer
  • modafinil or armodafinil, medicines used to treat sleepiness.

These medicines may be affected by diazepam or may affect how well it works. You may need different amounts of your medicine, or you may need to use different medicines. Your doctor or pharmacist will advise you.

Grapefruit juice has also been found to interfere with diazepam. You should avoid drinking grapefruit juice when you are receiving this medicine.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while you are being given DBL Diazepam Injection.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect DBL Diazepam Injection.

4. How is DBL Diazepam Injection given?

How much is given

Your doctor will decide what dose you will receive. This depends on your condition.

How it is given

DBL Diazepam Injection is usually given as a slow injection into a vein (intravenously). It can also be given as an injection into a muscle. DBL Diazepam Injection should only be given by a doctor, nurse or other trained person.

How long it is given for

DBL Diazepam Injection should only be given for short periods of 2 to 4 weeks. Your doctor will decide how long you will receive this medicine for.

If you are given too much DBL Diazepam Injection

This rarely happens as DBL Diazepam Injection is administered under the care of a highly trained doctor or nurse. Your condition will be carefully monitored following administration.

However, if you are given too much DBL Diazepam Injection you may feel extreme drowsiness, confusion and muscle weakness.

Your doctor or pharmacist has information on how to recognise and treat an overdose. Equipment is available to treat you if you experience severe side effects.

If you think that you have been given too much DBL Diazepam Injection, you may need urgent medical attention.

You should immediately:

  • contact your doctor, or
  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know during treatment with DBL Diazepam Injection?

Things you should do

  • Remind any doctor, nurse, dentist or pharmacist who is treating you that you are using DBL Diazepam Injection.

Things you should not do

  • Do not stop treatment with this medicine suddenly without speaking to your doctor.
Following long-term use of diazepam, the medicine may not be as effective as it used to be.
Your doctor may want to gradually reduce the amount of diazepam you have been receiving, before stopping it completely. Suddenly stopping this medicine after long term use or high doses, may cause unwanted side effects.
  • Do not take any other medicines, whether they are prescription or over-the-counter medicines, unless they have been approved or recommended by a doctor or pharmacist that knows you are being given DBL Diazepam Injection.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how DBL Diazepam Injection affects you.

Diazepam may cause dizziness, lightheadedness, drowsiness and disorientation in some people. It can also affect memory.

If you feel light-headed, dizzy or weak when getting out of bed or standing up, get up slowly.

Standing up slowly will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Additional precaution should be taken by elderly or unwell patients to reduce the risk of a fall.

Drinking alcohol

Tell your doctor if you drink alcohol regularly.

Do not drink alcohol while you are given diazepam.

Alcohol may increase the effects of diazepam.

If you drink alcohol, dizziness and/or drowsiness may be worse.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

If you are over 65 years of age you may have an increased chance of getting side effects.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Common side effects

Common side effectsWhat to do
General disorders and administration site conditions
  • fatigue
  • pain, swelling and redness at the injection site
  • fever
Nervous system
  • drowsiness
  • lack of coordination
  • dizziness
  • headache
  • light headedness
  • fainting
  • loss of memory
  • confusion
  • difficulty speaking/slurred speech
Skin related issues
  • rash (hives)
  • scaly itchy skin
  • blisters on skin
Changes in behaviour, thinking or mood
  • depressed mood
  • inattentiveness
  • lack of concentration
  • unpleasant dreams
Eye issues
  • double vision
Muscle related issues
  • muscle problems
Renal and urinary related issues
  • dryness of the mouth
  • difficulty urinating
Heart related issues
  • palpitations (irregular heart beat)
Stomach related issues
  • nausea, vomiting, diarrhoea or constipation
Speak to your doctor if you have any of these common side effects.

Serious side effects

Serious side effectsWhat to do
Respiratory issues
  • breathing difficulties, choking or coughing
  • fast breathing
Heart related issues
  • fast or irregular heart beat
Allergic reaction symptoms
  • 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
Changes in behaviour, thinking or mood
  • sudden anxiety or excitation
  • behavioural problems such as rage, anger
  • restlessness
  • agitation
  • irritability
  • hallucinations or delusions (seeing or hearing things that are not there)
  • abnormal behaviour
  • severe sleep disturbances
Blood related issues
  • unusual bleeding or bruising
Liver related issues
  • yellowing of the skin or eyes (jaundice)
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
You may need urgent medical attention.
Serious side effects are rare

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop treatment with any of your medicines.

7. Product details

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

What DBL Diazepam Injection contains

Active ingredient
(main ingredient)		diazepam
Other ingredients
(inactive ingredients)

propylene glycol

ethanol

water for injections

sodium hydroxide

Each ampoule contains 10 mg of diazepam per 2 mL.

DBL Diazepam Injection does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Do not use this medicine if you are allergic to any of these ingredients.

What DBL Diazepam Injection looks like

DBL Diazepam Injection is a clear, colourless to pale yellow liquid in a glass ampoule. (Aust R 115049).

DBL Diazepam Injection is available in the following strength:

  • 10 mg/2 mL

How is DBL Diazepam Injection stored

DBL Diazepam Injection should be stored in a cool dry place, protected from light, where the temperature stays below 25°C.

Who distributes DBL Diazepam Injection

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free number: 1800 675 229
www.pfizermedinfo.com.au

This leaflet was prepared in November 2021.

™ Trademark

© Pfizer Australia Pty Ltd 2021

Published by MIMS February 2022

BRAND INFORMATION

Brand name

DBL Diazepam Injection

Active ingredient

Diazepam

Schedule

S4

 

1 Name of Medicine

Diazepam.

2 Qualitative and Quantitative Composition

Each 2 mL ampoule contains diazepam 10 mg and the following inactive ingredients: propylene glycol 53% v/v, ethanol 31% v/v, in water for injections; pH 6.2 to 7.0.

Excipient(s) with known effect.

Ethanol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Benzodiazepine derivative is a colourless crystalline compound, insoluble in water. DBL Diazepam Injection is a clear colourless to pale yellow solution for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Management of anxiety disorders or for the short-term relief of 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 spasms 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.
Intravenous diazepam is useful in controlling status epilepticus and the spasms of tetanus. Diazepam is also used as pre-operative medication.

4.2 Dose and Method of Administration

Dosage.

Adults. The usual adult dose is 2 to 10 mg by intramuscular or intravenous injection repeated every three to four hours as required. In general, the maximum adult dose should not exceed 30 mg over an eight hour period.
Intravenous injections should be given into a large vessel, such as an antecubital vein, and the solution should be administered slowly at a rate not exceeding 5 mg/minute (see Section 4.4 Special Warnings and Precautions for Use).

Cardioversion.

To provide light anaesthesia and anterograde amnesia prior to cardioversion, 5 to 15 mg diazepam may be given by intravenous injection within 5 to 10 minutes before the procedure.

Endoscopic procedures.

To reduce anxiety, diazepam may be administered by slow intravenous injection immediately before the procedure; dosage should be titrated to obtain the desired sedative response. Generally, a dosage of up to 10 mg is adequate, but up to 20 mg intravenously may be given, particularly if opiates are not given concomitantly. If the intravenous route is not feasible, 5 to 10 mg may be given intramuscularly approximately 30 minutes before the procedure.

Anticonvulsant.

In the convulsing patient, it is preferred that diazepam be given intravenously. However, intramuscular injection may be used if intravenous administration is impossible. Initially, 5 to 10 mg may be given, repeated if necessary at 10 to 15 minute intervals up to a maximum dose of 30 mg. If necessary, a further dose may be repeated in 2 to 4 hours, however, residual active metabolites may persist and readministration should be made with this consideration.
Children. Benzodiazepines should not be given to children without careful assessment of the indication; the duration of treatment must be kept to a minimum.
Intravenous administration should be made slowly over a 3 minute period at a dosage not exceeding 0.25 mg/kg. After an interval of 15 to 30 minutes, the initial dose may be repeated.

Status epilepticus and severe recurrent convulsive seizures.

Slow intravenous administration is preferred.
Infants over 30 days of age and children under 5 years - 0.2 to 0.5 mg slowly every 2 to 5 minutes up to a maximum of 5 mg.
Children 5 years or older - 1 mg every 2 to 5 minutes up to a maximum of 10 mg. Repeat in 2 to 4 hours if necessary. EEG monitoring of the seizure may be helpful.

Tetanus.

Infants over 30 days of age and children under 5 years - 1 to 2 mg intramuscularly or by slow intravenous injection, repeated every 3 to 4 hours as necessary.
Children 5 years and older - 5 to 10 mg repeated every 3 to 4 hours as necessary.

Method of administration.

Diazepam may be administered intravenously or intramuscularly (deep into the muscle). However, absorption following intramuscular administration is slow and erratic; thus this route of administration should be avoided if possible. Too rapid injection or the use of veins with too small a lumen carries the risk of syncope, apnoea, hypotension, bradycardia or cardiac or respiratory arrest and thrombophlebitis. Resuscitation equipment must be kept ready at all times. Intra-arterial injection must be carefully avoided on account of the danger of necrosis and extravasation must be strictly avoided because venous thrombosis, phlebitis, local irritation, swelling or, less frequently, vascular changes may occur, particularly after rapid intravenous injection.
Lower doses should be used in the elderly, those with impaired hepatic or renal function or debilitated patients. 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.
Use in one patient on one occasion only and discard any residue.

Compatibility.

In general, the administration of diazepam by dilution or mixture with intravenous fluids or other drugs should be avoided. Diazepam may precipitate out of intravenous solutions and adsorbs to the plastic of intravenous bags and tubing. Where the administration of diazepam by intravenous infusion is indicated, glucose intravenous infusion 5% or sodium chloride intravenous infusion 0.9% of minimum volume 250 mL should be used. The amount of diazepam added should not exceed 20 mg. The required dose of diazepam should be quickly and thoroughly mixed with the total volume of the infusion medium and the infusion begun immediately. The possibility of overloading the patient with fluid should be kept in mind.

4.3 Contraindications

Diazepam is contraindicated:
In patients with a known hypersensitivity to benzodiazepines or any of the excipients in DBL Diazepam Injection.
In patients with severe respiratory failure, or chronic obstructive airways disease with incipient respiratory failure.
As sole therapy in psychosis including primary depressive disorders.
In patients with myasthenia gravis.
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.
The drug should not be administered intravenously to patients in shock, coma, patients with cardiac or respiratory insufficiency or those with acute alcoholic intoxication with depressed vital signs.

4.4 Special Warnings and Precautions for Use

Concomitant use of alcohol/ central nervous system (CNS) depressants.

Abilities may be impaired on the day following use. Patients should be advised that their tolerance for alcohol and other CNS depressants will be diminished. Concomitant use of diazepam with alcohol and/or with drugs, including opioids that have a depressive effect on the CNS should be avoided. These agents can enhance the clinical effects of diazepam and can possibly result in deep sedation, clinically significant respiratory and/or cardiovascular depression, coma, and death. These medications should either be eliminated or limit dosages and durations to the minimum required in the presence of diazepam.

Tolerance.

In general, benzodiazepines should be prescribed for short periods only (e.g. 2 to 4 weeks). Continuous long-term use of diazepam is not recommended. There is evidence that tolerance develops to the sedative effect 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).
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 patients with drug seeking behaviour.

Circulatory consequences.

Although hypotension has occurred only rarely, parenteral 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.

Memory impairment.

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

Disorientation.

Patients should be warned as to the possibility of prolonged disorientation due to the long half-life of diazepam. This may especially be true where diazepam is used for premedication.

Glaucoma.

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

Depression, psychosis and schizophrenia.

DBL Diazepam Injection is not recommended as primary therapy in patients with depression 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 behaviour and other adverse behavioural effects, acute rage, stimulation or excitement may occur; should such reactions occur, DBL Diazepam Injection should be discontinued. They are more likely to occur in children and the elderly.

Epilepsy.

When parenteral 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.

Medical history of drug/ alcohol abuse.

Abuse of benzodiazepines has been reported. Extreme caution must be exercised in administering diazepam to individuals with a history of alcohol or drug abuse, dependence on CNS depressants or those known to be addiction prone or those whose history suggests they may increase the dosage on their own initiative.

Dependence.

The use of benzodiazepines may lead to dependence 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.
Prolonged use of diazepam may cause a diminished response to the effects of benzodiazepines.

Withdrawal.

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 diazepam treatment is suddenly withdrawn, a temporary increase in sleep disturbance can occur (see Section 4.4 Special Warnings and Precautions for Use, Dependence).
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 can range from headache, diarrhoea, muscle pain, insomnia, extreme anxiety, tension, restlessness, confusion and irritability, 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, 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 an extended period of time. However, withdrawal symptoms have been reported following abrupt discontinuation of benzodiazepines administered continuously at therapeutic levels. Accordingly, DBL Diazepam Injection should be terminated by tapering the dose to minimise occurrence of withdrawal symptoms.
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. Withdrawal/ rebound symptoms may follow high doses for relatively short periods.

Rebound anxiety.

A transient syndrome whereby the symptoms that led to treatment with diazepam recur in an enhanced form. This may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety, sleep disturbances and restlessness.

Injection technique.

As a general rule, parenteral administration should only be done in a clinical setting (except in emergency cases) and measures for circulatory or respiratory life support should always be available.
When used intravenously, the following procedures should be adopted to reduce the possibility of venous thrombosis, phlebitis, local irritation, swelling and, rarely, vascular impairment: the solution should be injected slowly, taking at least one minute for each 5 mg (1 mL) given, into a large lumen vessel, such as an antecubital vein; do not use small veins such as those on the dorsum of the hand or wrist; extreme care should be taken to avoid intra-arterial administration or extravasation. Excessively rapid injection or administration into a small vein increases the risk of thrombophlebitis. Intra-arterial injection should be strictly avoided due to the danger of necrosis (see Section 4.2 Dose and Method of Administration).
Careful monitoring is recommended after intravenous administration of diazepam. Upon discharge, the patient should be accompanied by another individual and should be warned not to drive a vehicle after drug administration. See Section 4.7 Effects on Ability to Drive and Use Machines.
Intramuscular injection of diazepam can lead to a rise in serum creatinine phosphokinase activity, a maximum occurring twelve to twenty four hours after injection. (see Section 4.8 Adverse Effects (Undesirable Effects), Haematological). This fact should be taken into account in the differential diagnosis of myocardial infarction. In certain cases, IM route of administration should only be used if IV administration is not possible (see Section 4.2 Dose and Method of Administration).

General.

Dose of diazepam should be established individually based on the variable tolerance criteria of patients, particularly for those with physiological cerebral disorders (especially arteriosclerosis) or with cardiopulmonary insufficiency.

Impaired respiratory function.

Caution in the use of parenteral 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. Diazepam should be used with caution in patients with sleep apnoea.

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. Benzodiazepines may have a contributory role in precipitating episodes of hepatic encephalopathy in severe hepatic impairment.
As with other benzodiazepines, periodic blood counts and liver and kidney function tests are recommended, especially in the case of extended treatment.

Use in the elderly.

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. Extreme care must be used in administering injectable diazepam, particularly by the intravenous route, to the elderly, to very ill patients and to those with limited pulmonary reserve because of the possibility that apnoea and/or cardiac arrest may occur. Concomitant use of barbiturates, alcohol, or other CNS depressants increases depression, with increased risks of apnoea. Lower doses should be used for elderly and debilitated patients.

Paediatric use.

Efficacy and safety of parenteral diazepam have not been established in the neonate (30 days or less in age). Prolonged CNS depression has been observed in neonates due to inability to transform the drug.

Effects on laboratory tests.

Diazepam can inhibit binding of thyroxine and liothyronine to their binding proteins resulting in erroneously abnormal values from thyroid function tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacodynamic drug-drug interaction.

The benzodiazepines, including diazepam, produce additive CNS depressant effects when co-administered with other medications which themselves produce CNS depression, e.g. barbiturates, opioids, 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 (see Section 4.4 Special Warnings and Precautions for Use). Therefore, it should be borne in mind that the effect of these drugs may potentiate or be potentiated by the action of DBL Diazepam Injection. Enhanced side effects such as sedation and cardio-respiratory depression may also occur when diazepam is co-administered with any centrally acting depressants including alcohol. Alcohol should be avoided in patients receiving diazepam (see Section 4.4 Special Warnings and Precautions for Use). Concomitant use with alcohol is not recommended due to enhancement of the sedative effect.
See Section 4.9 Overdose for warning of other central nervous system depressants including alcohol.
There are several reports of severe hypotension, cardiorespiratory depression, excessive sedation or loss of consciousness in patients receiving combined treatment with clozapine and benzodiazepines, including diazepam. Concomitant use of diazepam and clozapine is not recommended.
Additive CNS depressant effects can be expected when combining phenothiazines and benzodiazepines; sedation, respiratory depression and airway obstruction have been reported with the combined use of levomepromazine and diazepam.
There are several reports of excessive sedation, loss of consciousness, severe hypotension, or cardiorespiratory depression sometimes resulting in death in patients receiving combined treatment with intramuscular olanzapine and benzodiazepines, including diazepam. Concomitant parenteral use is not recommended.
When combined with methadone diazepam may enhance euphoria, leading to an increased risk of abuse or dependence. Diazepam increased the subjective and sedative opioid effects of methadone in a manner that may heighten abuse potential. A significantly greater deterioration in reaction time was observed compared to methadone alone.
Reversible loss of control of Parkinson's disease has been seen in some patients treated with combined levodopa and diazepam.
The xanthines theophylline and caffeine oppose the sedative and possibly anxiolytic effects of diazepam partially through blocking of adenosine receptors.
Diazepam pretreatment changes the pharmacodynamics and pharmacokinetics of the anaesthetic ketamine. Ketamine N-demethylation was inhibited leading to a prolonged half-life and prolonged ketamine-induced sleeping time. In the presence of diazepam, a reduced ketamine concentration is required to achieve adequate anaesthesia.
The anti-cholinergic effects of other drugs including atropine and similar drugs, anti-histamines and anti-depressants may be potentiated.
Interactions have been reported between some benzodiazepines and anti-convulsants (e.g. diazepam with phenytoin or with carbamazepine), with changes in the serum concentration of the benzodiazepine or anti-convulsant. It is recommended that patients be observed for altered responses when benzodiazepines and anti-convulsants are prescribed together and that serum level monitoring of the anti-convulsant is performed more frequently.

Pharmacokinetic drug-drug interactions.

There is a potentially relevant interaction between diazepam and compounds which inhibit certain hepatic enzymes (particularly cytochrome P450 IIIA). Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation.
Diazepam undergoes oxidative metabolism, and consequently may interact with disulfiram, cimetidine, ketoconazole, fluvoxamine, fluoxetine or omeprazole diltiazem, idelalisib, clarithromycin, erythromycin, ritonavir and verapamil resulting in increased plasma levels of diazepam. Patients should be observed closely for evidence of enhanced benzodiazepine response during concomitant treatment with these drugs; some patients may require a reduction in benzodiazepine dosages.
The metabolism of diazepam and its main metabolite, desmethyldiazepam depends on the cytochrome P450 isozymes CYP3A4 and CYP2C19. Modulators of these enzymes may lead to changes in diazepam disposition and effects. Stronger interactions are seen with compounds that affect more than one of diazepam's oxidative metabolic pathways. Inhibitors of CYP3A4 and CYP2C19 decrease metabolic rate and may lead to higher than normal concentrations of diazepam and the desmethyl metabolite and consequently to increased/ prolonged sedation and anxiolytic effects. Such changes may exacerbate diazepam's effects in patients with increased sensitivity, e.g. due to their age, reduced liver function or treatment with other drugs that impair oxidation. Inducers of CYP3A4 and CYP2C19 may lead to lower than expected concentrations and hence to a lack of desired efficacy.
Effect of other drugs on the pharmacokinetics of diazepam.

Enzyme inhibitors.

Grapefruit juice contains strong inhibitors of CYP3A4. Diazepam exposure was strongly increased (AUC 3.2-fold; Cmax 1.5-fold) and time to reach maximum concentration was delayed when diazepam was given with grapefruit juice instead of water. This may result in excessive or prolonged sedation. Patients should be advised to avoid grapefruit juice while administering diazepam.
Antimycotic azole derivatives inhibit CYP3A4 and CYP2C19 pathways and lead to increased exposure to diazepam. In a clinical trial using a single dose of 5 mg diazepam, fluconazole increased the AUC of diazepam 2.5-fold and prolonged elimination half-life from 31 h to 73 h, while voriconazole increased the AUC of diazepam 2.2-fold and prolonged elimination half-life from 31 h to 61 h. In another clinical trial using a single dose of 5 mg diazepam, itraconazole had a more moderate effect (AUC increased by 15%, elimination half-life prolonged from 26.5 to 35.5 h). The increased exposure to diazepam may result in greater and more prolonged sedation. Therefore, it is recommended to avoid concomitant use of these drugs (including ketoconazole) with diazepam or reduce the dose of diazepam.
The serotonin reuptake inhibitor fluvoxamine also inhibits both of diazepam's CYP3A4 and CYP2C19 degradation pathways. In a clinical trial using a single dose of 10 mg diazepam, fluvoxamine increased not only the AUC of diazepam 3-fold and prolonged its elimination half-life from 51 h to 118 h, but also increased exposure and time to reach steady state of the desmethyl metabolite. Fluoxetine is a moderate inhibitor of CYP3A4. Fluoxetine showed a more moderate effect on diazepam AUC (approximately 50% increase) and did not affect psychomotor response because combined concentrations of diazepam and desmethyldiazepam were similar with and without fluoxetine. Fluvoxamine and fluoxetine may lead to increased and prolonged sedation. For patients taking fluvoxamine, a benzodiazepine metabolised via a non-oxidative pathway is recommended. Patients receiving fluoxetine with diazepam should be monitored closely.
Combined hormonal contraceptives appear to reduce the clearance (by 40%) and prolong elimination half-life (by 47%) of diazepam. Diazepam-induced psychomotor impairment in women on contraceptives may be higher during the 7-day menstrual pause when off the hormone preparation than when taking the contraceptive. Monitor the clinical response to diazepam in women taking concomitant oral contraception. There is some limited evidence that benzodiazepines can increase the incidence of break-through bleeding in women with hormonal contraceptives.
The proton pump inhibitor omeprazole, a CYP2C19 and CYP3A4 inhibitor, administered at a dose of 20 mg daily increased the diazepam AUC by 40% and the half-life by 36%; at a dose of 40 mg daily, omeprazole increased the diazepam AUC by 122% and the half-life by 130%. The elimination of desmethyldiazepam was reduced as well. The effect of omeprazole was seen in extensive but not slow metabolisers of CYP2C19. Esomeprazole (but not lansoprazole or pantoprazole) has the potential to inhibit the metabolism of diazepam to a similar degree as omeprazole. Patients administering these drugs with diazepam should be monitored closely and the dose of diazepam should be reduced if necessary.
The histamine H2-receptor antagonist cimetidine, an inhibitor of multiple CYP isozymes, including CYP3A4 and CYP2C19, reduces the clearance of diazepam and of desmethyldiazepam by 40 to 50%. This results in higher exposure to and a prolonged elimination half-life of diazepam and its main metabolite after single dosing and to higher steady-state concentrations after multiple dosing of diazepam. Enhanced sedation was seen with co-administration of cimetidine. Therefore, when used with cimetidine, a reduction in the dose of diazepam may be necessary. Ranitidine and famotidine do not affect the hepatic elimination of diazepam.
Disulfiram inhibits the metabolism of diazepam (median decrease in clearance 41%, increase in half-life 37%) and probably the further metabolism of diazepam's active metabolites. Enhanced sedative effects may result.
Antituberculosis therapy may change the disposition of diazepam. In the presence of isoniazid diazepam mean exposure (AUC) and half-life were increased (on average 33-35%) with the largest changes seen in subjects with slow-acetylator phenotype. When used with isoniazid, monitor patients and reduce the dose of diazepam if necessary.
The calcium channel blocker diltiazem, a substrate for the same CYP isozymes as diazepam and an inhibitor of CYP3A4, increased AUC (by approximately 25%) and prolonged half-life (by 43% in extensive CYP2C19 metabolisers) of diazepam with little differences between subjects with different CYP2C19 phenotypes. In the presence of diltiazem exposure to desmethyldiazepam also tended to increase. Exercise caution when using diazepam with diltiazem, irrespective of CYP2C19 metaboliser status.
The primary metabolite of idelalisib is a strong CYP3A4 inhibitor and increases the serum concentrations of diazepam so that dose reduction may have to be considered.
The psychostimulants modafinil and armodafinil induce CYP3A4 and inhibit CYP2C19; they may prolong the elimination of diazepam and cause excessive sedation. When used with these psychostimulants, monitor patients and reduce the dose of diazepam if necessary.
The use of other CYP3A or CYP2C19 inhibitors (such as clarithromycin, erythromycin, ritonavir and verapamil) with diazepam may lead to increased and prolonged sedation.

Enzyme inducers.

Rifampicin potently induces CYP3A4 and also has a significant accelerating effect on the CYP2C19 pathway. When dosed at 600 mg daily for 7 days, diazepam clearance was increased 4.3-fold and AUC decreased by 77%. A significant reduction in exposure to all diazepam metabolites was also observed. Doubling the daily rifampicin dose did not further increase its effect. Diazepam should only be used together with rifampicin if no therapeutic alternative exists.
Carbamazepine is a known inducer of CYP3A4 and accelerated elimination (increased clearance, reduced half-life) of diazepam 3-fold while increasing concentrations of desmethyldiazepam. This can result in a reduced effect of diazepam.
Effect of diazepam on the pharmacokinetics of other drugs. Diazepam has not been found to induce or inhibit metabolising enzymes. Nevertheless, some interactions with other drugs occur where diazepam is the precipitant.
Phenytoin therapy was associated with higher concentrations and increased phenytoin intoxication when combined with diazepam in some but not all studies. Monitoring of serum levels of phenytoin is recommended when initiating or discontinuing diazepam.
Diazepam may decrease the control of parkinsonian symptoms in patients taking levodopa. Diazepam should, therefore, be administered with caution to patients who are taking levodopa.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Reproductive studies in rats showed decreases in the number of pregnancies and in the number of surviving offspring following administration of oral doses of 100 mg/kg/day (22-fold the MRHD on a body surface area basis) to both males and females prior to and during mating and throughout gestation and lactation. No adverse effects were observed at 10 mg/kg/day (60 mg/m2/day, twice the MRHD).
(Category C)
Category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible.
The safety of diazepam for use in human pregnancy has not been established. Diazepam and its metabolites readily cross the placenta. Do not administer diazepam during the first trimester of pregnancy. 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, respiratory depression and hypothermia in the newborn infant. Continuous treatment during pregnancy and administration of high doses in connection with delivery should be avoided. Infants born of mothers taking benzodiazepines chronically during the later stages of pregnancy may develop physical dependence. 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 suckling, hypothermia and moderate respiratory depression 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).
Diazepam was found to be teratogenic in mice at intravenous doses of 45 mg/kg or greater and oral doses of 100 mg/kg or greater (both 10-fold the MRHD on a body surface area basis), as well as in hamsters at 280 mg/kg (41-fold the MRHD). The respective no-effect doses were 50 mg/kg (5-fold the MRHD) in mice and 200 mg/kg (30-fold the MRHD) in hamsters. Malformations included exencephaly, cranioschisis, kinking of the spinal cord, and cleft palate with and without cleft lip. Malformations were not observed in rats or rabbits at respective doses of up to 300 and 50 mg/kg/day (greater than 20-fold the MRHD). Delayed development has been reported in offspring from several animal species treated with diazepam during pregnancy or during pregnancy and lactation.
Published animal studies of some anaesthetic/analgesic/sedation drugs that are N-methyl-D-aspartate (NMDA) antagonists or GABAergic agonists have reported adverse effects on brain development in early life and late pregnancy (see Section 5.3 Preclinical Safety Data).
 Diazepam is excreted in human breast milk, and may cause drowsiness and feeding difficulties in the infant. Since diazepam passes into breast milk, injectable diazepam should not be administered to breastfeeding mothers, or breastfeeding should be suspended if the product is to be given regularly.

4.7 Effects on Ability to Drive and Use Machines

Sedation, amnesia, impaired concentration and impaired muscle function may adversely affect the ability to drive or operate machinery. Prior to receiving diazepam, patients should be warned not to operate dangerous machinery or drive motor vehicles until completely recovered. The physician should decide when these activities may be resumed.
If sleep duration is insufficient or alcohol and/or other CNS depressant drugs are consumed, the likelihood of impaired alertness may be increased (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.8 Adverse Effects (Undesirable Effects)

More common reactions.

The most commonly reported undesirable effects are fatigue, drowsiness, muscle weakness, dizziness and ataxia; they are usually dose related.

Less common reactions.

The following effects are encountered infrequently:

Haematological.

Blood dyscrasias including neutropenia, agranulocytosis, anaemia, leukopenia, thrombocytopenia.
Intramuscular injection (but not intravenous injection) may lead to a rise in serum creatinine phosphokinase activity, a maximum occurring twelve to twenty-four hours after injection. This fact should be taken into account in the differential diagnosis of myocardial infarction.

Cardiac disorders.

Hypotension, bradycardia, cardiac failure including cardiac arrest, tachycardia, palpitations, ventricular premature contractions and other arrhythmias.
The propylene glycol in DBL Diazepam Injection may lead to cardiovascular depression.

Vascular disorders.

Hypotension, circulatory depression.

Eye disorders.

Conjunctivitis, blurred vision, diplopia.

Ear and labyrinth disorders.

Vertigo.

Respiratory, thoracic and mediastinal disorders.

Decreased gag reflex, coughing, dyspnoea, respiratory depression including respiratory failure, hyperventilation, laryngospasm, and pain in the throat or chest.
The propylene glycol in DBL Diazepam Injection may lead to respiratory depression.

Renal and urinary disorders.

Urinary retention, difficulty in micturition, incontinence.

Gastrointestinal disorders.

Nausea and vomiting, diarrhoea, constipation, gastrointestinal disorders, dry mouth or hypersalivation.

Skin and subcutaneous tissue disorders.

Skin reaction, rash, urticaria, pruritus, photosensitivity.

Musculoskeletal and connective tissue disorders.

Muscular weakness, muscle cramps.

Hepatobiliary disorders.

Hepatic dysfunction, jaundice.

Nervous system disorders.

Amnesia, confusion, headache, slurred speech, consciousness decreased, lightheadedness, syncope, dysarthria, aphasia, tremor, nystagmus.
Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher doses. Amnestic effects may be associated with inappropriate behaviour.
Diazepam may produce increased incidence and severity of seizures, especially on withdrawal of diazepam in patients with epilepsy or a history of seizures.
Minor EEG changes, usually low voltage fast activity, of no known clinical significance, have been reported with benzodiazepine administration.

Psychiatric disorders.

Agitation, depression, libido disorder, flat affect, numbed emotion, irritability, confusional state, emotional and mood disturbances.
Paradoxical reactions such as restlessness, delusion, psychosis, anxiety, acute hyperexcitation, acute disorientation, nervousness, hostility, anger, panic, aggression, auditory and visual hallucinations, increased muscle spasticity, insomnia, rage, nightmares, abnormal dreams, sleep disturbances, stimulation, hyperactivity, inappropriate behaviour and other adverse behavioural effects have been reported; should these occur, use of diazepam should be discontinued. They are more likely to occur in children and in the elderly.
Emergence or worsening of mental depression, including suicidal ideation, also has been associated with benzodiazepine use, principally in patients with pre-existing depression.
Chronic use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena (see Section 4.4 Special Warnings and Precautions for Use).
Abuse of benzodiazepines has been reported (see Section 4.4 Special Warnings and Precautions for Use).

Immune system disorders.

Immediate hypersensitivity reactions.

General disorders and administration site conditions.

Body and joint pains, hyperpyrexia, hypothermia, fatigue.

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.

Injection site reactions.

Injection site reactions such as venous thrombosis, phlebitis, pain, local irritation and swelling, or less frequently, vascular changes, may occur (particularly after rapid intravenous injection). Intramuscular administration can result in local pain, in some cases accompanied by erythema, at the site of injection. Tenderness is relatively common.

Investigations.

Heart rate irregular, blood alkaline phosphatase increased, blood creatine phosphokinase increased, transaminases increased (see also Haematological above).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

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, dysarthria, nystagmus, mental confusion and lethargy. In more serious cases, symptoms may include ataxia, areflexia, apnoea, hypotonia, hypotension, cardiorespiratory depression, coma, and very rarely death. Coma may be more protracted and cyclical, particularly in elderly patients.
The respiratory depression effects associated with benzodiazepines are more serious in patients with respiratory disorders.
Benzodiazepines increase the effects of alcohol and other drugs with a depressive activity on the CNS. When combined with other CNS depressants, the effects of overdosage are likely to be severe and may prove fatal.

Treatment.

In the management of overdosage with any medication, it should be borne in mind that multiple agents may have been taken.
Treatment is purely supportive of respiratory and cardiovascular function, vital signs should be monitored and supportive measures should be applied according to the clinical status of the patient. Special attention should be paid to these functions in intensive care. Maintenance of adequate pulmonary ventilation is essential. The use of pressor agents intravenously may be necessary to combat hypotension. Fluids should be administered intravenously to encourage diuresis. 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. This drug should be administered only under strictly monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil must be used with extreme caution in the presence of drugs which can lower the convulsive threshold (e.g. tricyclic antidepressants). The use of flumazenil is not recommended in epileptic patients who have been treated with diazepam (or any other benzodiazepine). The reversal of the benzodiazepine effect could induce convulsions in such patients.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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 (GABA), a naturally occurring inhibitory neurotransmitter.
The effects of diazepam may result from action in the limbic and subcortical levels of the CNS. Benzodiazepines are capable of producing all levels of CNS depression (i.e. mild sedation to hypnosis to coma).

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Diazepam may be given by intravenous (IV) or intramuscular (IM) injection but absorption following intramuscular administration may be slow and erratic, depending on the muscle mass used and other factors. When diazepam is injected into the deltoid muscle, absorption is usually rapid and complete.

Distribution.

Plasma concentrations of diazepam and its active metabolites exhibit considerable interpatient variation, and therapeutic plasma concentrations are difficult to define. Diazepam is 98% protein bound in the plasma. Diazepam and its metabolites readily diffuse across the blood-brain barrier and placenta. They also appear in the milk of breastfeeding mothers.
During repeated dosing of diazepam, accumulation of diazepam and its active metabolites may occur. Accumulation continues until a steady-state plasma concentration is reached, which usually takes 5 days to 2 weeks after initiation of therapy.

Metabolism.

The plasma concentration time curve is biphasic, an initial rapid and extensive distribution phase with a half-life of up to three 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 three-fold in patients with cirrhosis.
The drug is metabolised in the liver to hydroxydiazepam (temazepam) and nordiazepam (t1/2 approximately 96 hours) and ultimately to oxazepam.
The elimination of diazepam after reaching steady-state levels is slow since active metabolites may remain in the blood for several days or even weeks, possibly resulting in persistent effects. The elimination half-life may be prolonged in the newborn infant, 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.

Excretion.

Diazepam is excreted mainly (about 70%) in the urine in free form or predominantly as glucuronide and sulphate metabolites.

5.3 Preclinical Safety Data

Effect of anaesthetic and sedative drugs on brain development in early life and late pregnancy.

Published studies in pregnant and juvenile animals demonstrate that the use of anaesthetic/analgesic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of rapid brain growth or synaptogenesis may result in neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis when exposed for longer than 3 hours. These studies included anaesthetic agents from a variety of drug classes. The clinical significance of these nonclinical findings is yet to be determined.

Genotoxicity.

Limited data from a number of studies have provided weak evidence of a genotoxic potential Diazepam has been shown to induce aneuploidy in sperm obtained from both mice and humans treated with approximately 10 mg/m2/day (less than the MRHD).

Carcinogenicity.

The carcinogenic 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 at 75 mg/kg/day (17- and 8-fold the MRHD on a body surface area basis, respectively). This was not observed in female rats and mice treated with 75 mg/kg/day or hamsters treated with 120 mg/kg/day (18-fold the MRHD).

6 Pharmaceutical Particulars

6.1 List of Excipients

Ethanol, propylene glycol, sodium hydroxide, water for injections.

6.2 Incompatibilities

See Section 4.2 Dose and Method of Administration, Compatibility.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

DBL Diazepam Injection 10 mg/2 mL is available in packs of 5 and 50 ampoules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


Benzodiazepine derivative. Chemical name: 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one. MW: 284.74.

CAS number.

439-14-5.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes