Consumer medicine information

Pethidine Juno Injection

Pethidine hydrochloride

BRAND INFORMATION

Brand name

Pethidine Juno

Active ingredient

Pethidine hydrochloride

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Pethidine Juno Injection.

SUMMARY CMI

Pethidine Juno 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.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I being treated with Pethidine Juno?

Pethidine Juno contains the active ingredient pethidine hydrochloride. Pethidine is pain killer that belongs to a group of medicines called opioid analgesics. It is most commonly used to relieve severe pain. It may also be used just before, or during, an operation, to help the anaesthetic work better.

For more information, see Section 1. Why am I being treated with Pethidine Juno? in the full CMI.

2. What should I know before treatment with Pethidine Juno?

Do not use if you have ever had an allergic reaction to pethidine 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 Pethidine Juno? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with pethidine 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 Pethidine Juno given?

Your doctor will decide what dose of pethidine you will receive. This depends on your condition and other factors, such as your age and weight.

More instructions can be found in Section 4. How is Pethidine Juno given? in the full CMI.

5. What should I know during treatment with Pethidine Juno?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are being given pethidine.
  • If you become pregnant while you are being treated with pethidine, tell your doctor immediately.
Things you should not do
  • Do not stop using this medicine suddenly. If you have been using pethidine for more than two weeks, you may experience unpleasant feelings if you stop pethidine suddenly.
Driving or using machines
  • Do not drive a car, operate machinery, or do anything else that could be dangerous until you know how pethidine affects you. Pethidine may cause drowsiness and impair coordination.
Drinking alcohol
  • Do not drink alcohol while you are being treated with pethidine.
Looking after your medicine
  • If you are being given Pethidine Juno while in hospital, it will be stored in the pharmacy or on the ward. Store below 25°C.

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

6. Are there any side effects?

Common side effects are mild and usually short lived. These include drowsiness, dizziness or unsteadiness, light-headedness, sweating or flushing, nausea or vomiting, constipation, hallucinations, pain and irritation at the injection site, blurred vision, dry mouth and mood changes. If you experience serious side effects such as severe drowsiness, slow or rapid heart beat, difficulty in urinating, slow or troubled breathing, severe weakness, agitation, twitching, jerking, seizures (fits), or unconsciousness, you may need urgent medical attention or hospitalisation.

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.

WARNING:

Limitations of use

Because of the risks associated with the use of opioids, pethidine should only be used when your doctor decides that other treatment options are not able to effectively manage your pain or you cannot tolerate them.

Hazardous and harmful use

Pethidine poses risks of abuse, misuse and addiction which can lead to overdose and death. Your doctor will monitor you regularly during treatment.

Life threatening respiratory depression

Pethidine can cause life-threatening or fatal breathing problems (slow, shallow, unusual or no breathing), even when used as recommended. These problems can occur at any time during use, but the risk is higher when first starting pethidine, after a dose increase, if you are older, or have an existing problem with your lungs. Your doctor will monitor you and change the dose as appropriate.

Use of benzodiazepines and other central nervous system (CNS) depressants, including alcohol

Using pethidine with other medicines that can make you feel drowsy such as sleeping tablets (e.g. benzodiazepines), other pain relievers, antihistamines, antidepressants, antipsychotics, gabapentinoids (e.g. gabapentin and pregabalin), cannabis and alcohol may result in severe drowsiness, decreased awareness, breathing problems, coma and death. Your doctor will minimize the dose and duration of use; and monitor you for signs and symptoms of breathing difficulties and sedation. You must not drink alcohol while using pethidine.



FULL CMI

Pethidine Juno Injection

Active ingredient(s): pethidine hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using Pethidine Juno. 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 Pethidine Juno.

Where to find information in this leaflet:

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

1. Why am I being treated with Pethidine Juno?

Pethidine Juno contains the active ingredient pethidine hydrochloride. Pethidine is a pain killer that belongs to a group of medicines called opioid analgesics. Pethidine acts in the brain and the spinal cord.

Pethidine Juno is most commonly used for the short-term management of severe pain. It may also be used just before, or during, an operation, to help the anaesthetic work better.

Your doctor may have prescribed pethidine for another reason.

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

2. What should I know before treatment with Pethidine Juno?

If you are not sure whether you should start treatment with pethidine, talk to your doctor or pharmacist.

Warnings

Do not use Pethidine Juno if you:

  • are allergic to pethidine, 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.
  • are an asthmatic, have breathing problems or have severe disease relating to the lungs
  • are suffering from a head injury or brain tumour
  • are suffering from a convulsive state such as status epileptics or tetanus, or if you have eclampsia or pre-eclampsia.
  • have an irregular heart beat (arrhythmia)
  • have diabetic acidosis
  • are undergoing treatment with, or have finished treatment in the last two weeks with, monoamine oxidase (MAO) inhibitors (e.g. selegiline, phenelzine, tranylcypromine, moclobemide)
  • have severe liver or kidney disease
  • have blood-coagulation problems, or are receiving treatment for this disorder (e.g. warfarin)
  • are suffering from acute alcoholism
  • have a blockage in the stomach and intestine (severe constipation) or have severe pain in the stomach with bloating, gut cramps and vomiting (paralytic ileus).

Check with your doctor if you:

  • have or have had any other medical conditions, especially the following:
    - lung or breathing problems
    - drug or alcohol abuse
    - a history of mental illness
    - gall bladder disease or gallstones
    - under-active thyroid (hypothyroidism)
    - adrenal gland tumour (phaechromocytoma) and/or when the adrenal glands are not working properly (Addison's disease)
    - low or high blood sugar, diabetes
    - epilepsy, convulsions, fits or seizures, or head injuries
    - glaucoma (increased pressure in the eye)
    - heart problems
    - liver or kidney impairment
    - severe inflammatory bowel disease or biliary colic
    - snoring or sleep apnoea (you temporarily stop breathing or have difficulty breathing while asleep)
  • take any medicines for any other condition
  • have allergies to any other medicines, foods, preservatives or dyes.

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 possible risks and benefits of you being given pethidine during pregnancy.

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

Your doctor will discuss the possible risks and benefits of you being given pethidine during breastfeeding.

Addiction

You can become addicted to pethidine even if you use it exactly as prescribed. Pethidine may become habit forming causing mental and physical dependence. If abused it may become less able to reduce pain.

Dependence

As with all other opioid containing products, your body may become used to you using pethidine. Using it for a long time (i.e. more than two weeks) may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop using pethidine suddenly, so it is important to use it exactly as directed by your doctor.

However, it is also important to keep your pain under control.

Your doctor can advise you on how to prevent and manage this.

Tolerance

Tolerance to pethidine may develop, which means that the effect of the medicine may decrease. If this happens, more may be needed to maintain the same effect.

Withdrawal

Continue using your medicine for as long as your doctor tells you. If you stop using this medicine suddenly, your pain may worsen and you may experience some or all of the following withdrawal symptoms:

  • nervousness, restlessness, agitation, trouble sleeping or anxiety
  • body aches, weakness or stomach cramps
  • loss of appetite, nausea, vomiting or diarrhoea
  • increased heart rate, breathing rate or pupil size
  • watery eyes, runny nose, chills or yawning
  • increased sweating.

Pethidine given to the mother during labour can cause breathing problems and signs of withdrawal in the newborn.

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 may interfere with pethidine and affect how it works. These include:

  • antidepressants or medicines for anxiety disorders, such as:
    - selective serotonin reuptake inhibitors (SSRIs)
    - serotonin and norepinephrine reuptake inhibitors (SNRIs)
    - tricyclic antidepressants (TCAs)
    - monoamine oxidase inhibitors (MAOIs) e.g. moclobemide, phenelzine, tranylcypromine
  • medicines used for migraines (triptans)
  • medicines used to prevent or treat nausea and vomiting (5-HT3 receptor antagonists)
  • selegiline, a monoamine oxidase inhibitor used to treat Parkinson's disease
  • warfarin, a medicine used to prevent blood clots
  • phenytoin or phenobarbital, medicines used to control fits or seizures
  • other medicines which may make you drowsy such as sleeping tablets (e.g. benzodiazepines, hypnotics), tablets to calm your nerves (e.g. sedatives), muscle relaxants, medicines to treat mental disorders, other opioid analgesics or strong painkillers, some antihistamines.
  • amphetamines
  • cimetidine, a medicine used to treat stomach ulcers and gastric reflux.

Medicines that may increase the effect of pethidine include:

  • macrolide antibiotics (e.g. erythromycin)
  • azole-antifungal agents (e.g. ketoconizole)
  • protease inhibitors or medication for HIV (e.g. ritonavir).

Medicines that may reduce the effect of pethidine include:

  • rifampicin (anti-tuberculosis medication)
  • carbamazepine and phenytoin (medicines used to control fits or seizures).

Your doctor will minimise the dose and duration of use; and monitor you for signs and symptoms of breathing difficulties and sedation.

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

Your doctor and pharmacist have more information on medicines to be careful with or avoid while you are receiving Pethidine Juno.

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

4. How is Pethidine Juno given?

How much is given

Your doctor will decide what dose of pethidine you will receive. This depends on your condition and other factors, such as your age and weight.

How it is given

Your doctor or nurse will usually administer Pethidine Juno Injection.

Pethidine Juno can be given as:

  • an injection into a muscle
  • a slow injection into a vein
  • an injection under the skin or
  • by a method called patient-controlled analgesia:
    - This method allows you, the patient, to control the amount of pethidine you wish to receive. On experiencing pain, you can press a button which allows a dose of pethidine to be administered to you. To prevent you receiving too much pethidine, there is a "lockout" period built into the pump which prevents continuous injection of pethidine.

Your doctor will decide the appropriate way for you to be given pethidine.

If you use too much (overdose)

Pethidine Juno is only recommended to be given for a maximum of 24 to 36 hours, however some people may need to receive it for longer.

If you or someone else have received too much (overdose) Pethidine Juno and experience one or more of the symptoms below, urgent medical attention is required. Keep the person awake by talking to them or gently shaking them every now and then. You should follow the above steps even if someone other than you have accidentally been given pethidine that was prescribed for you.

Symptoms of an overdose may include:

  • slow, unusual or difficult breathing
  • severe drowsiness, dizziness or unconsciousness
  • slow or weak heartbeat
  • nausea or vomiting
  • convulsions or fits (twitching or jerking)
  • severe weakness
  • pale and cold skin.

You should immediately:

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

When seeking medical attention, take this leaflet and remaining medicine with you to show the doctor. Also tell them about any other medicines or alcohol which have been taken.

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

5. What should I know during treatment with Pethidine Juno?

As pethidine may cause nausea and vomiting, your doctor is likely to prescribe medicine for you to take/receive before the pethidine, to stop you feeling sick.

Pethidine may also cause constipation, so your doctor is likely to prescribe laxatives to prevent this happening.

Things you should do

  • Tell any doctors, dentists and pharmacists who are treating you that you are being given Pethidine Juno.
  • If you are about to be started on any new medicine, tell your doctor, dentist and pharmacist that you are being given Pethidine Juno.
  • If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are being treated with Pethidine Juno.
  • If you become pregnant while you are being treated with pethidine, tell your doctor or pharmacist.
  • Tell your doctor, pharmacist or nurse if you have any concerns about being given pethidine.

Things you should not do

  • Do not give Pethidine Juno to anyone else, even if they have the same condition as you.
  • Do not use Pethidine Juno to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not stop using Pethidine Juno or lower the dosage without checking with your doctor or pharmacist. If you have been using pethidine for more than two weeks, you may experience unpleasant feelings if you stop it suddenly. Your doctor will probably want you to gradually reduce the amount of pethidine you are using, before stopping it completely.
  • Do not take any other medicines, whether they are prescription or over-the-counter medicines, unless they have been prescribed or recommended by a doctor or pharmacist who knows you are being given pethidine.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Pethidine Juno affects you.

Pethidine may cause drowsiness and impairment of coordination in some people. Do not drive a car, operate machinery, or do anything else that could be dangerous if you are drowsy or feeling uncoordinated.

Drinking alcohol

Tell your doctor if you drink alcohol.

You must not drink alcohol while using pethidine. Do not drink alcohol while you are undergoing treatment with pethidine unless otherwise advised by your doctor or pharmacist, as drowsiness and coordination impairment may be worse.

Looking after your medicine

If you are being given Pethidine Juno while in hospital, it will be stored in the pharmacy or on the ward.

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

Do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine (as relevant)

Do not use this medicine after the expiry date.

Pethidine Juno should not be given to you if the packaging is torn or shows signs of tampering.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

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.

If you get any side effects, do not stop pethidine without first talking to your doctor or pharmacist.

Common side effects

Common side effectsWhat to do
  • drowsiness
  • dizziness or unsteadiness
  • disorientation
  • light-headedness
  • sweating or flushing
  • nausea and/or vomiting
  • constipation
  • hallucinations
  • pain and irritation at the injection site
  • blurred vision
  • dry mouth
  • mood changes
Speak to your doctor if you have any of these less common side effects and they worry you.
Mostly these are mild and short lived.

Serious side effects

Serious side effectsWhat to do
  • severe drowsiness
  • slow or rapid heart beat
  • difficulty in urinating
  • slow or troubled breathing
  • severe weakness
  • agitation
  • twitching
  • jerking
  • seizures (fits)
  • unconsciousness
  • itchy rash
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 or hospitalization.

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 taking any of your medicines.

7. Product details

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

What Pethidine Juno contains

Active ingredient
(main ingredient)		Pethidine hydrochloride
Other ingredients
(inactive ingredients)		Sodium hydroxide
Hydrochloric Acid
Water for Injections

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

Pethidine Juno does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

What Pethidine Juno looks like

Pethidine Juno is a clear, colourless, sterile solution in ampoules.

It is available in the following strength:

  • 100 mg/2 mL AUST R 340377

Who distributes Pethidine Juno

Juno Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121

This leaflet was prepared in April 2024.

Published by MIMS May 2024

BRAND INFORMATION

Brand name

Pethidine Juno

Active ingredient

Pethidine hydrochloride

Schedule

S8

 

1 Name of Medicine

Pethidine hydrochloride.

2 Qualitative and Quantitative Composition

2 mL sterile solution of pH 3.5 - 6.0 containing 100 mg of pethidine hydrochloride (50 mg/mL).

Excipients with known effect.

None.
For the full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Injection solution. Clear, colourless solution.

4 Clinical Particulars

4.1 Therapeutic Indications

The short-term management of severe pain for which other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain.
Pre-operative medication.
Analgesic adjunct in general anaesthesia.
Obstetric analgesia.

4.2 Dose and Method of Administration

Pethidine hydrochloride may be administered by subcutaneous, intramuscular or slow intravenous injection. Pethidine Juno contains no antimicrobial agent. It should be used only once and any residue discarded.
For intravenous administration the dosage should be decreased and the injection administered very slowly as a dilute solution. When pethidine is given parenterally, especially by the intravenous route, the patient should be lying down. While the subcutaneous route is suitable for occasional use, intramuscular administration is preferred for repeated doses.
When administered intravenously, an opioid antagonist and facilities for assisted or controlled respiration should be immediately available during and following the injection.

Adult.

Analgesia.

25 to 100 mg by SC or IM injection or 25 to 50 mg by slow IV injection every 3 to 4 hours (see Section 4.4 Special Warnings and Precautions for Use).
The dose should be adjusted according to the severity of pain and the response of the patient.
Dosage reduction may be necessary in the elderly.

Premedication.

50 to 100 mg by SC or IM injection or 25 to 50 mg by slow IV injection (see Section 4.4 Special Warnings and Precautions for Use).

Obstetric analgesia.

50 to 100 mg by SC or IM injection at intervals of 1 to 3 hours if necessary. Up to 3 doses may be given in 24 hours.

Renal and hepatic dysfunction.

Dosage reduction and/or increased dosage intervals may be necessary in patients with renal or hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).

Paediatric.

Analgesia.

0.5 to 2 mg per kg bodyweight IM (maximum 100 mg) every 3 to 4 hours.

Premedication.

1 to 2 mg per kg bodyweight IM (maximum 100 mg).

Neonates.

Metabolism and excretion of pethidine is reduced in the neonate compared with adults. The safety of pethidine in neonates has not been established and no dosage regimen can be recommended.

4.3 Contraindications

Hypersensitivity to pethidine.
Patients who are taking or have taken a mono amine oxidase inhibitor (including selegiline) within the previous fourteen days. The combination of mono amine oxidase inhibitors and pethidine has caused hypotension, hypertension, excitation, rigidity, hyperpyrexia and/or convulsions, and in some cases fatalities have been reported. This combination should be avoided.
Patients with severe respiratory disease and acute respiratory disease. Respiratory depression, or patients in whom respiratory reserve is significantly depleted (e.g. severe emphysema, severe chronic bronchitis, kyphoscoliosis, acute bronchial asthma, chronic airway disease).
Convulsive states such as status epilepticus, tetanus and strychnine poisoning, due to the stimulatory effects of pethidine on the spinal cord.
Pre-eclampsia, eclampsia.
Cardiac arrhythmias, especially supraventricular tachycardias; cor pulmonale. Pethidine has a possible vagolytic action which may produce a significant increase in the ventricular response rate.
Diabetic acidosis where there is a danger of coma.
Acute alcoholism or delirium tremens.
Severe liver disease, incipient hepatic encephalopathy.
Known or suspected gastrointestinal obstruction, including paralytic ileus (see Section 4.4 Special Warnings and Precautions for Use).
Head injury, raised intracranial pressure (may cause diagnostic and monitoring problems; also hypercapnia associated with depressed respiration may increase intracranial pressure by itself); brain tumour.
Patients with a low platelet count, coagulation disorders or receiving anticoagulant treatment.

Continuous intravenous infusion.

The administration of pethidine via continuous intravenous infusion in patients with renal impairment is contraindicated.

Patient controlled analgesia.

The administration of pethidine via patient controlled analgesia (PCA) in young children and adults with poor cognitive function is contraindicated. The administration of pethidine via PCA in patients with renal impairment is contraindicated.

4.4 Special Warnings and Precautions for Use

Serious and/or life threatening reactions have been associated with the use of pethidine. The recommendations in Section 4.4 Special Warnings and Precautions for Use should be carefully observed. These reactions include respiratory depression, coma, convulsions (possibly due to elevated levels of norpethidine) and hypotension.

Hazardous and harmful use.

Pethidine Juno contains the opioid pethidine and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed pethidine at recommended doses.
The risk of addiction is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) or mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for opioid abuse or addiction prior to being prescribed pethidine.
All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Opioids are sought by people with addiction and may be subject to diversion. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the safe storage and proper disposal of any unused drug (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal). Caution patients that abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal.
Patients should be advised not to share Pethidine Juno with anyone else.

Respiratory depression.

Serious, life-threatening or fatal respiratory depression can occur with the use of opioids even when used as recommended. It can occur at any time during the use of pethidine, but the risk is greatest during initiation of therapy or following an increase in dose. Patients should be monitored closely for respiratory depression at these times.
The risk of life-threatening respiratory depression is also higher in elderly, frail, or debilitated patients (see Special risk patients), in patients with existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma) and in patients with hepatic and renal impairment (see Use in hepatic and renal impairment). Opioids should be used with caution and with close monitoring in these patients (see Section 4.2 Dose and Method of Administration). The use of opioids is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression (see Section 4.3 Contraindications).
The risk of respiratory depression is greater with the use of high doses of opioids, especially high potency and modified release formulations, and in opioid naive patients. Initiation of opioid treatment should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief. Careful calculation of equianalgesic doses is required when changing opioids or switching from immediate release to modified release formulations, together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response. Patients with severe pain may tolerate very high doses of pethidine but may exhibit respiratory depression should their pain suddenly subside.
If serious respiratory depression requiring treatment occurs in a patient who is physically dependent on opioids, an opioid antagonist should be administered with extreme care at a dose of 10 - 20% of the recommended initial dose. The administration of the usual dose will precipitate an acute withdrawal syndrome in these individuals, the severity of which will depend on the degree of physical dependence and the dose of antagonist administered. The use of opioid antagonists in such individuals should be avoided if possible.

Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol.

Concomitant use of opioids and benzodiazepines or other CNS depressants, including alcohol, may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of pethidine with CNS depressant medicines, such as other opioid analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics and other CNS depressants, should be reserved for patients for whom other treatment options are not possible. If a decision is made to prescribe pethidine concomitantly with any of the medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Patients should be followed closely for signs and symptoms of respiratory depression and sedation. Patients and their caregivers should be made aware of these symptoms. Patients and their caregivers should also be informed of the potential harms of consuming alcohol while being treated with pethidine.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of medicine-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Advise both patients and caregivers about the risks of respiratory depression including CSA and sleep-related hypoxaemia, and sedation when pethidine is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs).
Advise patients not to drive or operate heavy machinery during concomitant use of the benzodiazepine or other CNS depressant. these activities should not be contemplated until the day following the last dose of pethidine (see Section 4.7 Effects on Ability to Drive and Use Machines). Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use of opioids in chronic (long-term) non-cancer pain (CNCP).

Opioid analgesics have an established role in the treatment of acute pain, cancer pain and palliative and end-of-life care. Current evidence does not generally support opioid analgesics in improving pain and function for most patients with chronic non-cancer pain. The development of tolerance and physical dependence and risks of adverse effects, including hazardous and harmful use, increase with the length of time a patient takes an opioid. The use of opioids for long-term treatment of CNCP is not recommended.
The use of an opioid to treat CNCP should only be considered after maximised non-pharmacological and non-opioid treatments have been tried and found ineffective, not tolerated or otherwise inadequate to provide sufficient management of pain. Opioids should only be prescribed as a component of comprehensive multidisciplinary and multimodal pain management.
Opioid therapy for CNCP should be initiated as a trial in accordance with clinical guidelines and after a comprehensive biopsychosocial assessment has established a cause for the pain and the appropriateness of opioid therapy for the patient (see Hazardous and harmful use, above). The expected outcome of therapy (pain reduction rather than complete abolition of pain, improved function and quality of life) should be discussed with the patient before commencing opioid treatment, with agreement to discontinue treatment if these objectives are not met.
Owing to the varied response to opioids between individuals, it is recommended that all patients be started at the lowest appropriate dose and titrated to achieve an adequate level of analgesia and functional improvement with minimum adverse reactions. Immediate-release products should not be used to treat chronic pain, but may be used for a short period in opioid-naive patients to develop a level of tolerance before switching to a modified-release formulation. Careful and regular assessment and monitoring is required to establish the clinical need for ongoing treatment. Discontinue opioid therapy if there is no improvement of pain and/or function during the trial period or if there is any evidence of misuse or abuse. Treatment should only continue if the trial has demonstrated that the pain is opioid responsive and there has been functional improvement. The patient's condition should be reviewed regularly and the dose tapered off slowly if opioid treatment is no longer appropriate (see Ceasing opioids).

Tolerance, dependence and withdrawal.

Neuroadaptation of the opioid receptors to repeated administration of opioids can produce tolerance and physical dependence. Tolerance is the need for increasing doses to maintain analgesia. Tolerance may occur to both the desired and undesired effects of the opioid.
Physical dependence, which can occur after several days to weeks of continued opioid usage, results in withdrawal symptoms if the opioid is ceased abruptly or the dose is significantly reduced. Withdrawal symptoms can also occur following the administration of an opioid antagonist (e.g. naloxone) or partial agonist (e.g. buprenorphine). Withdrawal can result in some or all of the following symptoms: dysphoria, restlessness/agitation, lacrimation, rhinorrhoea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, increasing pain, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, increased blood pressure, increased respiratory rate and increased heart rate. Abrupt withdrawal of pethidine in those physically dependent may precipitate withdrawal syndrome, including convulsions.
When discontinuing pethidine in a person who may be physically-dependent, the drug should not be ceased abruptly but withdrawn by tapering the dose gradually (see Ceasing opioids; see Section 4.2 Dose and Method of Administration).
In an individual physically dependent on opioids, the administration of the usual dose of an opioid antagonist will precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of antagonist administered. The use of opioid antagonists in such individuals should be avoided if possible. If an opioid antagonist must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and only 10 to 20% of the usual initial dose administered.

Accidental ingestion/exposure.

Accidental ingestion or exposure of Pethidine Juno, especially by children, can result in a fatal overdose of pethidine. Patients and their caregivers should be given information on safe storage and disposal of unused pethidine (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal).

Hyperalgesia.

Hyperalgesia may occur with the use of opioids, particularly at high doses. Hyperalgesia may manifest as an unexplained increase in pain, increased levels of pain with increasing opioid dosages or diffuse sensitivity not associated with the original pain. Hyperalgesia should not be confused with tolerance (see Tolerance, dependence and withdrawal). If opioid induced hyperalgesia is suspected, the dose should be reduced and tapered off if possible. A change to a different opioid may be required.

Ceasing opioids.

Abrupt discontinuation or rapid decreasing of the dose in a person physically dependent on an opioid may result in serious withdrawal symptoms and uncontrolled pain (see Tolerance, dependence and withdrawal). Such symptoms may lead the patient to seek other sources of licit or illicit opioids. Opioids should not be ceased abruptly in a patient who is physically dependent but withdrawn by tapering the dose slowly. Factors to take into account when deciding how to discontinue or decrease therapy include the dose and duration of the opioid the patient has been taking, the type of pain being treated and the physical and psychological attributes of the patient. A multimodal approach to pain management should be in place before initiating an opioid analgesic taper. During tapering, patients require regular review and support to manage any increase in pain, psychological distress and withdrawal symptoms.
There are no standard tapering schedules suitable for all patients and an individualised plan is necessary. In general, tapering should involve a dose reduction of no more than 10 percent to 25 percent every 2 to 4 weeks (see Section 4.2 Dose and Method of Administration). If the patient is experiencing increased pain or serious withdrawal symptoms, it may be necessary to go back to the previous dose until stable before proceeding with a more gradual taper.
When ceasing opioids in a patient who has a suspected opioid use disorder, the need for medication assisted treatment and/or referral to a specialist should be considered.

Seizures.

Seizures may result from prolonged exposure or high doses. Patients with known seizure disorders should be carefully observed, as pethidine use may aggravate pre-existing convulsions. (See Section 4.3 Contraindications). If dosage is escalated substantially above recommended levels because of tolerance development, convulsions may occur in individuals without a history of convulsive disorders.

Pethidine associated neurotoxicity (PAN).

Pethidine associated neurotoxicity (PAN) is a range of excitatory central nervous system effects including tremor, hallucinations, seizures and mood changes attributed to the metabolite norpethidine (see Section 4.8 Adverse Effects (Undesirable Effects)). As norpethidine is primarily cleared by renal excretion, pethidine should be used with caution in patients with impaired renal function, the elderly, the very young and in patients receiving concomitant therapy with drugs such as phenobarbital or phenylhydantoin. The problems of PAN are essentially dose-related, so pethidine should not be used for periods greater than 24 to 36 hours.
The risk of PAN is increased in a situation in which the patient may receive large doses of pethidine, as with patient controlled analgesia (PCA). Caution should therefore be taken in patients receiving pethidine by PCA. Frequent clinical assessment and recording of the amount of drug used is required to minimise such risks. Clinical experience suggests that patients with normal renal function receiving more than 1000 mg/24 hrs of pethidine are at particular risk of developing PAN. Patients receiving over 800 mg/24 hrs of pethidine should be usually monitored for early signs of norpethidine toxicity (e.g. twitching, anxiety).

Patient controlled analgesia (PCA).

The use of pethidine in patient controlled analgesia (PCA) should be reserved for short term (24 to 36 hours) use in patients with normal renal function who have adverse reactions to morphine. Morphine is the opioid of choice for PCA.

Serotonin syndrome.

The development of serotonin syndrome (SS), which is potentially life-threatening, has been reported with opioid use, including with pethidine. These reports generally occurred when pethidine was used concomitantly with serotonergic drugs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Serotonin syndrome may include mental status changes (e.g. agitation, hallucinations, coma, confusion), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia, diaphoresis), neuromuscular abnormalities (e.g. hyperreflexia, incoordination, rigidity, tremor, myoclonus), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea).
If serotonin syndrome is suspected, a dose reduction or discontinuation of at least one of the serotonergic medicines being taken should be considered depending on the severity of symptoms.

Head injuries.

Use is not recommended in patients with head injury and increased intracranial pressure. Respiratory depressant effects and ability to increase cerebrospinal fluid pressure may be exaggerated, and the clinical course obscured.

Adrenal insufficiency.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Phaeochromocytoma.

The administration of pethidine to patients with phaeochromocytoma may result in a hypertensive crisis.

Prostatic hypertrophy or urethral stricture.

Pethidine should be used with caution in patients with prostatic hypertrophy or urethral stricture.

Hypothyroidism, Addison's disease.

Pethidine should be given with caution and the initial dose should be reduced in patients with hypothyroidism or Addison's disease.

Hypoglycaemia/hyperglycaemia.

Hypoglycaemia and hyperglycaemia have been reported during opioid use. This should be considered when diabetics require treatment with pethidine.

Gastrointestinal conditions.

Pethidine is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
Pethidine may obscure the diagnosis and clinical course in patients with acute abdominal conditions. The risk of toxic megacolon may be increased in patients with severe inflammatory bowel disease.
Only use when necessary, and then with caution, in biliary colic, operations on the biliary tract and acute pancreatitis in view of the spasmogenic properties of pethidine on the biliary tract and the sphincter of Oddi. Pethidine may make surgical exploration of the common bile duct difficult.
Pethidine produces reduced gastric emptying and the risk of aspiration may be expected to increase, whether associated with pethidine induced CNS depression/coma or during or after general anaesthesia, as for example a patient in labour who proceeds to caesarean section.

Cardiovascular effects.

Reduced cardiac output may lead to reduced hepatic perfusion and diminished metabolism of pethidine leading to accumulation of pethidine with possible toxic results.
A transient rise in blood pressure and systemic vascular resistance as well as an increased heart rate may be caused by pethidine, therefore it is not recommended for pain relief in cardiac infarction.
The administration of pethidine may result in profound hypotension in patients whose ability to maintain blood pressure is compromised by depleted blood volume or concurrent administration of certain anaesthetics or phenothiazines. Pethidine may also produce orthostatic hypotension in ambulatory patients.

Ophthalmic effects.

There are conflicting reports about the effect of pethidine on the eye. Some reports state that pethidine and its congeners produce miosis, whereas others indicate that these drugs tend to produce mydriasis or no pupillary change. Until the effects are better defined, intraocular tension should be monitored in patients with glaucoma who receive pethidine.

Administration rate and dosage.

Pethidine should not be administered by intravenous injection unless resuscitative equipment and opioid antagonists are readily available.
Large doses and/or rapid intravenous administration of pethidine may produce rapid onset respiratory depression, including central sleep apnoea (CSA) and sleep-related hypoxaemia, apnoea, hypotension, peripheral circulatory collapse, bradycardia (due to stimulation of medullary vagal nuclei) or even cardiac arrest. Consider decreasing the opioid dosage using best practices for opioid taper. Pethidine injections should be given slowly and preferably as a diluted solution.
Inadvertent intra-arterial administration of pethidine can produce severe necrosis and gangrene.

Risks of concomitant use or discontinuation of cytochrome P450 3A4 inhibitors and inducers.

Concomitant use of pethidine with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g. erythromycin), azole-antifungal agents (e.g. ketoconazole), and protease inhibitors (e.g. ritonavir), may increase plasma concentrations of pethidine and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression (see Respiratory depression) particularly when an inhibitor is added after a stable dose of pethidine p is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in pethidine treated patients may increase pethidine plasma concentrations and prolong opioid adverse reactions. When using pethidine with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in pethidine treated patients, monitor patients closely at frequent intervals and consider dosage reduction of pethidine until stable drug effects are achieved (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Concomitant use of pethidine with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease pethidine plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to pethidine. When using pethidine with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider adjusting the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Fatal interaction with monoamine oxidase inhibitors.

Pethidine is contraindicated in patients who are receiving monoamine oxidase (MAO) inhibitors or those who have recently received such agents. Therapeutic doses of pethidine have occasionally precipitated unpredictable, severe, and occasionally fatal reactions in patients who have received such agents within 14 days. The mechanism of these reactions is unclear, but may be related to a preexisting hyperphenylalaninemia. Some have been characterized by coma, severe respiratory depression, cyanosis, and hypotension, and have resembled the syndrome of acute narcotic overdose. Serotonin syndrome with agitation, hyperthermia, diarrhoea, tachycardia, sweating, tremors and impaired consciousness may also occur. In other reactions the predominant manifestations have been hyperexcitability, convulsions, tachycardia, hyperpyrexia, and hypertension.
Do not use pethidine in patients taking MAOIs or within 14 days of stopping such treatment.

Special risk patients.

Caution and an initial reduction in dose is recommended in patients who are elderly or debilitated and those with severely impaired pulmonary, hepatic or renal function and those with hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy or urethral stricture.

Use in hepatic and renal impairment.

Caution and an initial reduction in dose is recommended in patients with severely impaired hepatic or renal function.
Since pethidine is metabolized in the liver and excreted via the kidneys, reduced hepatic and renal function may lead to accumulation of the toxic metabolite, norpethidine.

Use in the elderly.

Caution and an initial reduction in dose is recommended in patients who are elderly or debilitated.
The elderly demonstrate an increased sensitivity to opioids relative to younger patients. Reduced hepatic function, renal function and plasma protein binding may contribute to the elevated plasma levels found in elderly subjects. Lower doses or an increased dosing interval may be sufficient to provide effective analgesia in elderly patients.
Pethidine associated neurotoxicity (PAN) is a range of excitatory central nervous system effects including tremor, hallucinations, seizures and mood changes attributed to the metabolite norpethidine (see Section 4.8 Adverse Effects (Undesirable Effects)). As norpethidine is primarily cleared by renal excretion, pethidine should be used with caution in patients with impaired renal function, the elderly, the very young and in patients receiving concomitant therapy with drugs such as phenobarbital or phenylhydantoin. The problems of PAN are essentially dose-related, so pethidine should not be used for periods greater than 24 to 36 hours.

Paediatric use.

Pethidine associated neurotoxicity (PAN) is a range of excitatory central nervous system effects including tremor, hallucinations, seizures and mood changes attributed to the metabolite norpethidine (see Section 4.8 Adverse Effects (Undesirable Effects)). As norpethidine is primarily cleared by renal excretion, pethidine should be used with caution in patients with impaired renal function, the elderly, the very young and in patients receiving concomitant therapy with drugs such as phenobarbital or phenylhydantoin. The problems of PAN are essentially dose-related, so pethidine should not be used for periods greater than 24 to 36 hours.

Effect on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

CNS depressants.

The depressant effects of pethidine are potentiated by other CNS depressants such as other opioid analgesics, alcohol, barbiturates, chloral hydrate, benzodiazepines, gabapentinoids, cannabis, sedatives, antihistamines, antipsychotics neuroleptics (e.g. phenothiazines, butyrophenones) tricyclic antidepressants, centrally-active anti-emetics and general anaesthetics (see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol).

Phenothiazines.

CNS toxicity, hypotension and respiratory depression may occur when pethidine and phenothiazines are given together. In eclampsia the combination has been reported to induce recurrence of seizures (see Section 4.3 Contraindications; Section 4.6, Use in pregnancy).

Monoamine oxidase inhibitors (MAOIs).

Pethidine is contraindicated in patients who are taking or have taken a mono amine oxidase inhibitor within the previous fourteen days (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use). Excitation, sweating, rigidity, hypertension or hypotension, and coma have occurred when pethidine is given to patients who are taking MAOIs. On occasion this interaction has proved fatal. Examples of MAOIs include phenelzine, tranylcypromine and linezolid. Selegiline, a MAO B inhibitor, has also been reported to interact with pethidine, causing delirium, restlessness, sweating and rigidity.

Amphetamines.

Concurrent use with amphetamines, which have some MAO inhibiting activity, is not recommended because of the risk of serious reactions similar to those reported with other MAOIs.

Delayed absorption/ paracetamol.

The actions of pethidine on the gastrointestinal tract may influence absorption of other drugs. For example, paracetamol absorption may be reduced.

Phenytoin/ phenobarbital.

Concomitant phenytoin or phenobarbital therapy may increase the metabolism of pethidine, which may produce increased CNS effects due to norpethidine and reduce analgesia. (See Section 4.8 Adverse Effects (Undesirable Effects)).

Coumarin, indanedione.

The effects of these derivative anticoagulants may be increased.

Cimetidine.

Cimetidine inhibits metabolism of pethidine and therefore increases plasma concentration.
Also see Section 6.2 Incompatibilities.

Serotonergic drugs.

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Drugs that affect the serotonergic neurotransmitter system include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, and MAOIs.

Inhibitors of CYP3A4 and CYP2B6.

The concomitant use of pethidine and CYP3A4 or CYP2B6 inhibitors such as macrolide antibiotics (e.g. erythromycin), azole-antifungal agents (e.g. ketoconazole), and protease inhibitors (e.g. ritonavir), can increase the plasma concentration of pethidine, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of pethidine and CYP2B6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of pethidine is achieved (see Section 4.4 Special Warnings and Precautions for Use).
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the pethidine plasma concentration will decrease, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to pethidine.
If concomitant use is necessary, consider dosage reduction of pethidine until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 or CYP2B6 inhibitor is discontinued, consider adjusting the pethidine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

CYP3A4 and CYP2B6 inducers.

The concomitant use of pethidine and CYP3A4 inducers, or CYP2B6 inducers such as rifampin, carbamazepine and phenytoin can decrease the plasma concentration of pethidine, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to pethidine (see Section 4.4 Special Warnings and Precautions for Use). After stopping a CYP3A4 or CYP2B6 inducer, as the effects of the inducer decline, the pethidine plasma concentration will increase, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
If concomitant use is necessary, consider adjusting the pethidine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 or CYP2B6 inducer is discontinued, consider pethidine dosage reduction and monitor for signs of respiratory depression.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category C)
Although pethidine is commonly used for pain relief in obstetrics, it is known to cross the placenta, and may cause respiratory depression in the neonate. An opioid antagonist may be required to reverse this depression. Opioid analgesics should only be used during labour after weighing the needs of the mother against the risk to the foetus.
Elimination of both pethidine and norpethidine is prolonged in pregnant women, with the possibility of accumulation of both compounds following multiple doses of pethidine in labour. The foetus will be exposed to high levels of pethidine and norpethidine because of a continued diffusion gradient from mother to foetus, with the potential for clinically significant levels of norpethidine being achieved in the newborn. Metabolism and excretion of pethidine in the neonate is significantly reduced in comparison to adults, therefore accumulation and toxic levels may be reached following low doses.
In eclampsia the combination of pethidine with phenothiazines has been reported to induce recurrence of seizures rather than stopping them. Therefore, the use of pethidine in eclampsia and pre-eclampsia is not recommended (see Section 4.3 Contraindications).
Animal reproduction studies have not been conducted with pethidine hydrochloride and safe use in pregnancy prior to labour has not been established in respect to possible adverse effects on foetal development.
Infants born of mothers who have been taking pethidine chronically may exhibit withdrawal symptoms. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhoea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
 Pethidine appears in breast milk. As the concentrations in breast milk following usual therapeutic doses in the mother have not been determined and the clinical significance is not known, pethidine administration to nursing mothers is not recommended.

4.7 Effects on Ability to Drive and Use Machines

Since pethidine may cause drowsiness and general impairment of co-ordination, ambulatory patients should be cautioned against driving or operating machinery. Driving and operating dangerous machinery should not be contemplated until the day following the last dose of pethidine.

4.8 Adverse Effects (Undesirable Effects)

As with other opioid analgesics respiratory depression is the major hazard of parenteral pethidine therapy. Other adverse experiences include:

More common.

Central nervous system.

Light headedness, dizziness, sedation, sweating, disorientation, bizarre feelings, hallucinations, psychosis. These effects seem to be more prominent in ambulatory patients and those not experiencing severe pain and may be relieved by reducing the dose slightly and lying the patient down.

Gastrointestinal.

Nausea, vomiting, constipation.

Less common.

Central nervous system.

Euphoria, dysphoria, weakness, headache, delirium, insomnia, anxiety, hyperactivity or agitation, convulsions or tremor, drowsiness, coma, vertigo, uncoordinated muscle movements, respiratory depression, cold clammy skin, pallor, visual disturbances, miosis, depression, mental clouding, occasional reports of mydriasis. Inadvertent injection around a nerve trunk may cause sensorineural effects, which is usually, but not always, transitory.
Pethidine associated neurotoxicity (PAN) is a range of excitatory central nervous system effects including tremor, hallucinations, seizures and mood changes attributed to the metabolite norpethidine. As norpethidine is primarily cleared by renal excretion, pethidine should be used with caution in patients with impaired renal function, the elderly, the very young and in patients receiving concomitant therapy with drugs such as phenobarbital or phenylhydantoin. The problems of PAN are essentially dose-related.

Gastrointestinal.

Dry mouth, anorexia, biliary tract spasm, decreased gastric emptying.

Genitourinary.

Urinary retention, antidiuretic effect, anuria, reduced libido and/or potency.

Cardiovascular.

Facial flushing, pallor, vasodilation, tachycardia, bradycardia, palpitations, faintness, syncope, hypertension, hypotension, orthostatic hypotension, gangrene following inadvertent intra arterial administration.

Dermatological.

Hypersensitivity causing pruritus, urticaria and other skin rashes, erythema, oedema, pain at injection site, local tissue irritation and induration following subcutaneous administration (especially after repeated injection), fibrosis of muscle tissue with frequent repetition of intramuscular injection.

Hepatic.

Increased biliary tract pressure, choledochoduodenal sphincter spasm.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

Symptoms.

Overdosage is characterised by respiratory depression which may progress to Cheyne-Stokes respiration and/or cyanosis. Concomitant CNS depression may be present, as may extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin and/or hypothermia, bradycardia and hypotension.
In severe overdosage, particularly following rapid intravenous administration, apnoea, circulatory collapse, cardiac arrest, respiratory arrest and death may occur.
Complications such as pneumonia, shock and/or pulmonary oedema may also prove fatal.
Overdosage of pethidine may produce mydriasis rather than miosis (pupillary constriction). Toxic effects of pethidine may be excitatory, especially in patients who have developed tolerance to the depressant effects of the drug. These patients may exhibit dry mouth, increased muscular activity, muscle tremors and twitches, tachycardia, delirium with disorientation, hallucinations and, occasionally, grand mal seizures.

Treatment.

Since respiratory arrest may result either through direct depression of the respiratory centre or as the result of hypoxia, primary attention should be given to the establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation.
The opioid antagonist, naloxone, is a specific antidote. Naloxone (see package information for full information) should be administered intravenously, simultaneously with respiratory resuscitation. As the duration of effect of naloxone may be considerably shorter than that of pethidine repeated administration may be necessary.

Note.

The administration of the usual dose of opioid antagonist to a patient who is physically dependent on opioids will precipitate an acute withdrawal syndrome, the severity of which will depend on the degree of physical dependence and the dose of antagonist administered. If serious respiratory depression requiring treatment occurs in a patient who is physically dependent on opioids, an opioid antagonist should be administered with extreme care at a dose of 10 - 20% of the usual initial dose.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pethidine is a synthetic opioid with analgesic and sedative properties, its actions qualitatively similar to those of morphine. In addition to providing analgesia, pethidine, in common with other opioids, produces respiratory depression, drowsiness, sedation, mood changes, euphoria, dysphoria, mental clouding, nausea, vomiting and electroencephalographic changes. Large doses of pethidine may cause excitation and convulsions.
After parenteral administration, 75 to 100 mg of pethidine has comparable analgesic, euphoric and respiratory depressant effects to 10 mg of morphine. Pethidine has a more rapid onset of action but shorter duration of analgesic effect than does morphine.
The depressant effect of pethidine on the cough reflex may be less than morphine at equianalgesic doses. Pethidine has spasmolytic as well as spasmogenic effects and may produce less constipation than morphine. Atropine like effects such as dry mouth and blurred vision have been reported with pethidine.
Norpethidine, which is a major metabolite, is twice as potent as pethidine as a convulsive agent and half as active as an analgesic.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Pethidine undergoes rapid first pass metabolism after oral administration and although well absorbed from the gastrointestinal tract it is considerably less effective orally than parenterally. Absorption after intramuscular use may be erratic; 80% or more after a 100 mg intramuscular dose of pethidine has been shown to be absorbed over 6 hours with a Tmax of 24 minutes. Analgesia may persist for 2 to 4 hours following intramuscular and subcutaneous administration.

Distribution.

Though there is limited information on the distribution of pethidine, data indicate that it is extensively distributed extravascularly, primarily in rapidly perfused tissues.
Pethidine has a volume of distribution of 4 L/kg and is approximately 70% plasma protein bound.

Metabolism.

Pethidine is mainly metabolised in the liver, primarily undergoing hydrolysis to pethidinic acid followed by partial conjugation with glucuronic acid. Other metabolic pathways include demethylation to norpethidine, which may be hydrolysed to norpethidinic acid and then conjugated with the glucuronic acid.

Excretion.

Pethidine has an average plasma elimination half-life of approximately 3.2 ± 0.8 hours. The elimination of pethidine may be prolonged in patients with cirrhosis, acute viral hepatitis or other hepatic dysfunction.
Approximately 5% of an IV dose of pethidine is excreted in the urine unchanged. Acidification of the urine enhances the excretion of unchanged pethidine and the metabolite norpethidine, but is not recommended as treatment in cases of overdose.
The elimination half-life of norpethidine is prolonged in patients with impaired renal function, persons over 60 years and neonates, which may lead to accumulation and toxic effects, such as seizures, agitation, irritability, tremors, twitching and myoclonus.
Elimination of both pethidine and norpethidine is prolonged in pregnant women, with the possibility of accumulation of both compounds following multiple doses of pethidine in labour. The foetus will be exposed to high levels of pethidine and norpethidine because of a continued diffusion gradient from mother to foetus, with the potential for clinically significant levels of norpethidine being achieved in the newborn.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Water for injections, sodium hydroxide or hydrochloric acid for pH adjustment.

6.2 Incompatibilities

Pethidine has been reported to be physically or chemically incompatible with thiopentone solutions and solutions containing aminophylline, amylobarbitone sodium, heparin sodium, methicillin sodium, morphine sulfate, nitrofurantoin, phenobarbital sodium, phenytoin sodium, aciclovir sodium, imipenem, frusemide, doxorubicin hydrochloride, idarubicin hydrochloride, sodium bicarbonate, sodium iodide or sulphafurazole diethanolamine.
Pethidine is also incompatible with alkalis, iodine and iodides.

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.

6.5 Nature and Contents of Container

2 mL glass ampoules in packs of 5, 10* and 50*.
* Not supplied in Australia.

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.


CAS number.

50-13-5.
The chemical name for pethidine hydrochloride is ethyl 1-methyl-4-phenylpiperidine-4-carboxylate hydrochloride. Empirical formula C15H21NO2.HCl. MW: 283.8.

7 Medicine Schedule (Poisons Standard)

Controlled drug (Schedule 8).

Summary Table of Changes