Consumer medicine information

Pethidine Injection BP

Pethidine hydrochloride

BRAND INFORMATION

Brand name

AstraZeneca Pethidine Injection BP

Active ingredient

Pethidine hydrochloride

Schedule

S8

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some of the common questions people ask about Pethidine. It does not contain all the information that is known about Pethidine.

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

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Pethidine against the benefits they expect it will have for you.

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

Keep this leaflet. You may need to read it again.

What PETHIDINE is for

Pethidine is a powerful drug used to relieve pain and produce sleepiness.

It can be used for the short-term management of severe pain or it can be used before painful operations to reduce the pain that you feel. It can also be used during childbirth to ease the pain of contractions.

Pethidine belongs to a group of medicines called opioid (narcotic) analgesics.

Pethidine works by changing the pain messages that are sent to the brain.

Your doctor will have explained why you are being treated with pethidine and told you what dose you will be given.

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

Your doctor may prescribe this medicine for another use.

Ask your doctor if you want more information.

Pethidine can be addictive. The risk of addiction is increased in people with a history of substance abuse or mental illness. The risk also increases the longer the drug is used and with higher doses. However, it is also important to keep your pain under control. Your doctor can advise you on how to best manage this.

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

Before you are given PETHIDINE

When you must not be given it

This medicine must not be given to you if you have an allergy to pethidine or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction to pethidine 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.

Pethidine Injection BP should not be given to you if you:

  • have respiratory diseases such as severe emphysema, severe chronic bronchitis, kyphoscoliosis, acute asthma or chronic airway disease.
  • are suffering from a head injury or brain tumour
  • are suffering from a convulsive state such as status epilepticus 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 eg selegeline, phenelzine, tranylcypromine, moclobemide
  • have severe liver disease
  • have blood-thinning problems, or are receiving treatment for this disorder (eg warfarin)
  • are suffering from acute alcoholism.

Pethidine Injection BP should not be given to you after the expiry date (EXP) printed on the pack. If this medicine is used after the expiry date has passed, it may not work as well.

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

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

Before you are given it

Tell your doctor or pharmacist if you have any allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes.

Tell your doctor or pharmacist if you are pregnant or intend to become pregnant. Your doctor or pharmacist will discuss the possible risks and benefits of being given pethidine during pregnancy.

Tell your doctor or pharmacist if you are breast-feeding or plan to breast-feed. Pethidine passes into breast milk and therefore there is a possibility that your baby may be affected. Your doctor or pharmacist will discuss the possible risks and benefits of being given pethidine during breastfeeding.

Tell your doctor or pharmacist if you have any medical conditions, especially the following:

  • lung or breathing problems
  • a history of alcohol or drug abuse
  • a history of mental illness
  • under-active thyroid (hypothyroidism) and/or adrenal gland (Addison’s disease)
  • adrenal gland tumour (phaeochromocytoma)
  • a history of epilepsy, fits (seizures) or head injuries.
  • glaucoma (increased pressure in the eye)
  • heart problems
  • severe liver or kidney impairment
  • severe inflammatory bowel dsease or biliary colic
  • diabetes

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

Taking other medicines

You must tell your doctor if you are taking any other medicines, including medicines that you buy at the pharmacy, supermarket or health food shop.

Some medicines and pethidine may interfere with each other. These include:

  • antidepressants or medicines for anxiety disorders, such as:
    - selective serotonin reuptake inhibitors (SSRIs) or
    - serotonin and norepinephrine reuptake inhibitors (SNRIs),
    - tricyclic antidepressants (TCAs)
    - monoamine oxidase inhibitors (MAOIs) ie moclobemide, phenelzine, tranylcypromine
  • medicines used for migraines (triptans)
  • medicines used to prevent or treat nausea and vomiting (5-HT3 receptor antagonists)
  • selegeline, a monoamine oxidase inhibitor used to treat Parkinson’s disease
  • alcohol
  • 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, tablets to calm your nerves, muscle relaxants, medicines to treat mental disorders, other strong painkillers, some antihistamines, general anaesthetics
  • amphetamines
  • cimetidine, a medicine used to treat stomach ulcers and gastric reflux.

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 may have more information on medicines to be careful with or avoid while you are receiving Pethidine Injection BP.

If you have not told your doctor about any of these things, tell them before you are given any pethidine.

How PETHIDINE is 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

Pethidine will be given to you by injection by your doctor or s nurse.

The injection may be given into a vein, into a muscle or sometimes under the skin.

You should be generally be lying down when the injection is given, especially if it is given into a vein.

Overdose

The doctor or nurse giving you Pethidine will be experienced in its use, so it is extremely unlikely that you will be given too much.

However, the first signs of overdosage is usually a marked slowing of your breathing. In some cases fits, severe drowsiness, severe weakness, slow heart beat or pale and cold skin can occur.

Pethidine doses should be carefully worked out, so problems with overdosage are unlikely. There is another drug, called naloxone, which can be used to reverse the effects of too much Pethidine if needed.

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26 in Australia) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Pethidine Injection BP. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using it

Things you must not do

Tell any other doctors, dentists, and pharmacists who are treating you that you are being given Pethidine Injection BP.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are being given Pethidine Injection BP.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are undergoing therapy with Pethidine Injection BP.

If you plan to become pregnant while you are undergoing therapy with pethidine, tell your doctor or pharmacist.

Talk to your doctor or pharmacist about these possibilities if you think they may bother you.

Things you must not do

Do not give Pethidine Injection BP to anyone else, even if they have the same condition as you.

Do not use Pethidine Injection BP to treat any other complaints unless your doctor or pharmacist tells you to.

Do not stop using pethidine, 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 drive or operate machinery while you are being given Pethidine. Pethidine may cause drowsiness and impair your coordination and ability to make decisions. Driving and operating dangerous machinery should not be contemplated until the day following the last dose of pethidine.

Do not drink alcohol while you are being given Pethidine.

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 pethidine.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are being treated with Pethidine.

Pethidine helps most people suffering severe pain, but it may have unwanted side-effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects. If you are over 65 years of age you may have an increased chance of getting side effects.

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

After you have been given Pethidine you will probably feel light-headed, dizzy, sleepy and you may feel quite strange, especially if you are not lying down.

Tell your doctor or nurse if you notice any of the following side effects and they worry you.

  • pain or irritation at the injection site
  • drowsiness
  • dizziness, light headedness or unsteadiness
  • disorientation
  • mood changes or hallucinations
  • sweating
  • blurred vision
  • dry mouth
  • nausea (feeling sick) and/or vomiting
  • constipation.

These are the more common side effects of pethidine. Mostly these are mild and short-lived.

If any of the following happen, tell your doctor or nurse immediately or go to Accident and Emergency at your nearest hospital:

  • slow or troubled breathing
  • severe drowsiness or weakness
  • slow or rapid heart rate
  • difficult in urinating
  • itchy rash
  • agitation
  • muscle twitching, jerking or fits (seizures)
  • loss of consciousness.

These may be serious side effects. You may need urgent medical attention or hospitalisation.

Some people may get other side effects after being given pethidine.

Tell your doctor if you notice anything else that is making you feel unwell.

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

Storage

If you are storing Pethidine Injection BP at home, it should be kept in the original pack in a cool dry place where the temperature stays below 25°C.

Do not store it or any other medicine in the bathroom or near a sink. Heat and dampness can destroy some medicines.

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

Do not leave it in the car on hot days.

Disposal

Make sure that you return to your doctor or pharmacist any injections that have passed the use by (expiry) date marked on the pack, or if you have any left over when your doctor says you no longer need to be given pethidine.

Product Description

Each Pethidine Injection BP ampoule contains pethidine hydrochloride 50mg/mL as the active ingredient in Water for Injection BP. Sodium hydroxide is used for pH adjustment.

In the USA pethidine is known as meperidine.

Pethidine Polyamp® Luer Fit® is available in a 2mL plastic ampoule in packs of 10 and 50.

Manufacturer

Juno Pharmaceuticals Pty Ltd
42 Kelso Street,
Cremorne,
VIC – 3121

This leaflet was updated on 20 May 2020.

Australian Registration Number: 100mg/2mL AUST R 48345

Published by MIMS July 2020

BRAND INFORMATION

Brand name

AstraZeneca Pethidine Injection BP

Active ingredient

Pethidine hydrochloride

Schedule

S8

 

1 Name of Medicine

Pethidine hydrochloride.

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.

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.

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.

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.

4.3 Contraindications

Hypersensitivity to pethidine.
Patients who are taking or have taken a monoamine oxidase inhibitor (including selegiline) within the previous fourteen days. The combination of monoamine 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. Similarly, pethidine should not be used in pre-eclampsia or 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.
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.

4.4 Special Warnings and Precautions for Use

Serious and/or life threatening reactions have been associated with the use of pethidine. The recommendations, see 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 Injection BP 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 Injection BP 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 naïve 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. 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.

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 nonpharmacological 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 naïve 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).

Accidental ingestion/exposure.

Accidental ingestion or exposure of Pethidine Injection BP, 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.

Other.

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.
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.
Hyperglycaemia has been reported with opioid agonists. This should be considered when diabetics require treatment with these agents.
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.
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.
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.
Inadvertent intra-arterial administration of pethidine can produce severe necrosis and gangrene.
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.
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 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.
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). Signs of SS may include clonus, agitation, diaphoresis, tremor, hyperreflexia, hypertonia and temperature elevation.

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.
Seizures may result from high doses. Patients with known seizure disorders should be carefully observed, as pethidine use may aggravate pre-existing convulsions (Section 4.3 Contraindications).
The administration of pethidine to patients with phaeochromocytoma may result in a hypertensive crisis.

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.
Reduced cardiac output may lead to reduced hepatic perfusion and diminished metabolism of pethidine leading to accumulation of pethidine with possible toxic results.

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.

Monoamine oxidase inhibitors (MAOIs).

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. 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.

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.

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.
 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.

4.8 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 (phenytoin). The problems of PAN are essentially dose-related.

Gastrointestinal.

Dry mouth, anorexia, biliary tract spasm.

Genitourinary.

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

Cardiovascular.

Facial flushing, 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.

4.2 Dose and Method of Administration

Pethidine hydrochloride may be administered by subcutaneous, intramuscular or slow intravenous injection. Pethidine Injection BP 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.

4.7 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.

4.9 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.

7 Medicine Schedule (Poisons Standard)

Controlled drug (Schedule 8).

6 Pharmaceutical Particulars

6.1 List of Excipients

Water for injections, sodium hydroxide 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 polyethylene ampoules (Polyamp DuoFit) 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.

Summary Table of Changes