Consumer medicine information

Prodeinextra

Paracetamol; Codeine phosphate hemihydrate

BRAND INFORMATION

Brand name

Prodeinextra

Active ingredient

Paracetamol; Codeine phosphate hemihydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Prodeinextra.

SUMMARY CMI

Prodeinextra®

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 using Prodeinextra?

Prodeinextra contains the active ingredients paracetamol and codeine phosphate hemihydrate. Prodeinextra is used to relieve acute moderate pain and fever. For more information, see Section 1. Why am I using Prodeinextra? in the full CMI.

2. What should I know before I take Prodeinextra?

Do not take if you have ever had an allergic reaction to Prodeinextra 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 I use Prodeinextra? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Prodeinextra 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 do I take Prodeinextra?

The standard dose for adults and children aged 12 years and over for this medicine is 2 caplets, taken every 4 to 6 hours if necessary.

More instructions can be found in Section 4. How do I use Prodeinextra? in the full CMI.

5. What should I know while using Prodeinextra?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Prodeinextra.
  • Talk to your doctor about pain control if the medicine is not helping.
  • Tell your doctor if you become pregnant while taking Prodeinextra.
Things you should not do
  • Do not take more than the recommended dose unless your doctor tells you to.
  • Do not take more than 8 tablets a day.
  • Do not give Prodeinextra to children under 12.
  • Do not take high doses of the medicine for long periods of time unless you doctor tells you to.
Driving or using machinesBe careful before you drive or use any machines or tools until you know how Prodeinextra affects you.
Prodeinextra may cause dizziness, drowsiness or light-headedness in some people.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • Patients treated with this medication should not drink alcohol whilst taking this medication.
Looking after your medicine
  • Store below 30°C.
  • Store in a cool, dry place away from young children.

For more information, see Section 5. What should I know while using Prodeinextra? in the full CMI.

6. Are there any side effects?

  • Tell your doctor or pharmacist immediately if you notice any of the following side effects 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. They may be the signs of an allergic reaction.
  • Tell your doctor or pharmacist if you notice any of the following and they worry you: nausea or vomiting, constipation, drowsiness or dizziness. These are the more common side effects of your medicine. They are usually mild.

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

Prodeinextra should only be used if your doctor decides other treatment options are not able to effectively manage your pain or you cannot tolerate them.

Hazardous and harmful use

Prodeinextra contains codeine which may be habit forming. Prodeinextra poses risks of abuse, misuse and addiction which can lead to overdose and death. Your doctor will assess your risks and monitor you regularly during treatment.

Life threatening respiratory depression

Serious, life-threatening, or fatal respiratory depression (shallow or difficulty breathing) may occur with the use of Prodeinextra even when used as recommended. These problems can occur at any time during use, but the risk is higher when first starting Prodeinextra and 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 other medicines while using Prodeinextra

Using Prodeinextra 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 regularly for signs and symptoms of breathing difficulties and sedation. You must not drink alcohol while taking Prodeinextra.



FULL CMI

Prodeinextra®

Active ingredient(s): paracetamol and codeine phosphate hemihydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Prodeinextra. 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 Prodeinextra.

Where to find information in this leaflet:

1. Why am I using Prodeinextra?
2. What should I know before I take Prodeinextra?
3. What if I am taking other medicines?
4. How do I take Prodeinextra?
5. What should I know while using Prodeinextra?
6. Are there any side effects?
7. Product details

1. Why am I using Prodeinextra?

Prodeinextra contains the active ingredients paracetamol and codeine phosphate hemihydrate.

Prodeinextra is a type of analgesic. Paracetamol and codeine work together to stop the pain messages from getting through to the brain. Paracetamol also acts in the brain to help reduce fever.

Prodeinextra is used to relieve acute moderate pain and fever and is intended for short term use.

2. What should I know before I take Prodeinextra?

Warnings

Do not take Prodeinextra if:

  • you are allergic to paracetamol or codeine phosphate hemihydrate, or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.
  • you have severe and/or acute respiratory diseases
  • you have unstable asthma or emphysema, respiratory depression (shallow breathing) or respiratory insufficiency (difficulty breathing).
  • you have bronchitis
  • you have liver failure
  • you have Glucose-6-phosphate-dehydrogenase deficiency (an enzyme deficiency)
  • you are a known CYP 2D6 ultra-rapid metaboliser (a fast metaboliser of codeine by the CYP 2D6 enzyme)
  • you have a history of intolerance to this medicine
  • you have diarrhoea caused by antibiotics or poisoning

Do not take Prodeinextra if you have a history of drug dependence, including alcohol dependence.

Do not take Prodeinextra during the third trimester of pregnancy.

Do not take it if you are in labour, especially if the baby is premature.

Do not take Prodeinextra if you are allergic to morphine or oxycodone.

Do not give Prodeinextra to children under 12 years.

Do not give Prodeinextra to children aged between 12-18 years who have undergone tonsillectomy and/or adenoidectomy to treat sleep apnoea.

Do not take it if you are breastfeeding or planning to breastfeed.

Do not take it after the expiry date (EXP) printed on the pack. If you take it after the expiry date has passed, it may not work as well.

Do not take it if the packaging is damaged or shows signs of tampering.

Check with your doctor or pharmacist if you have or have had any of the following medical conditions:

  • heart, lung, liver or kidney problems
  • low blood pressure
  • difficulty breathing, wheezing, chronic cough, asthma, or other chronic breathing conditions
  • compromised respiratory function (due to emphysema, kyphoscoliosis or obesity)
  • known analgesic intolerance
  • a history of drug dependence, including alcohol dependence
  • pre-existing opioid dependence
  • chronic alcohol use including recent cessation of alcohol intake
  • low glutathione reserves
  • Gilbert's syndrome
  • stomach, gallbladder, urinary or bowel conditions
  • chronic constipation
  • recent stomach, intestines or urinary tract surgery
  • prostate problems
  • problems with your adrenal gland or thyroid
  • multiple sclerosis
  • head injury or trauma
  • convulsions, fits or seizures.

Tell your doctor or pharmacist if you plan to have surgery.

Tell your doctor or pharmacist if you drink large quantities of alcohol.

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 or pharmacist if you are pregnant or intend to become pregnant.

Do not take Prodeinextra during the third trimester of pregnancy.

Do not take it if you are in labour, especially if the baby is premature.

Prodeinextra contains codeine, which may produce withdrawal effects in the newborn baby.

Do not take it if you are breastfeeding or planning to breastfeed.

Prodeinextra passes into breast milk and there is a possibility your baby may be affected.

Addiction

You can become addicted to Prodeinextra even if you take it exactly as prescribed. Prodeinextra 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 taking Prodeinextra. Taking it may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop taking Prodeinextra suddenly, so it is important to take it exactly as directed by your doctor.

Tolerance

Tolerance to Prodeinextra 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 taking your medicine for as long as your doctor tells you. If you stop having 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.

Prodeinextra 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 affect how Prodeinextra works. These include:

  • medicines causing sleepiness or drowsiness
  • tranquillisers (medicines for anxiety and nerves)
  • gabapentinoids, hypnotics, cannabis and centrally-active anti-emetics
  • benzodiazepines (medicines used as sedatives or to treat anxiety)
  • medicines containing alcohol (ethanol), e.g. some cough syrups
  • medicines used to treat depression
  • anticholinergics (medicines for stomach cramps/spasms, travel sickness, Parkinson's disease)
  • antipsychotics (medicines used to treat mental illnesses)
  • monoamine oxidase inhibitors (medicines used to treat depression) taken within the last 10 days
  • salicylates or non-steroidal antiinflammatory drugs (NSAIDS), such as aspirin or ibuprofen
  • medicines which thin the blood
  • medicines to treat epilepsy
  • other pain relief medication
  • medicines used to treat high blood pressure
  • medicines used to relax muscles
  • medicines used to treat diarrhoea, nausea or vomiting
  • propantheline, a medicine used to treat stomach ulcers
  • cholestyramine (medicine used to treat bile problems and/or high cholesterol)
  • chelating resin
  • medicines used to treat alcohol and/or opioid dependence (e.g. naltrexone, buprenorphine or methadone)
  • chloramphenicol (medicine used to treat ear and eye infections)
  • flucloxacillin, zidovudine or rifampicin (medicines used to treat infections).
  • medicines used to control electrolytes levels in kidney disease

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

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

4. How do I take Prodeinextra?

How much to take

  • The standard dose for adults and children aged
    12 years and over for this medicine is 2 caplets, taken every 4 to 6 hours if necessary.
  • Follow the instructions provided.
  • Do not exceed the recommended dosage.
  • You should not take more than 8 caplets in a 24 hour period.

Ask your doctor or pharmacist if you are unsure of the correct dose for you.

They will tell you exactly how much to take.

If you take the wrong dose, Prodeinextra may not work as well and your problem may not improve.

How to take Prodeinextra

  • Swallow the caplets whole with a little water or other liquid.

When to take Prodeinextra

  • If you are not sure when to take it, ask your doctor or pharmacist.

How long to take Prodeinextra

Do not take this medicine for longer than 48 hours (for children aged 12-17 years) or for more than 3 days, except on medical advice.

  • Ask your doctor or pharmacist if you are not sure how long to take the medicine for.

If you forget to take Prodeinextra

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

Do not take a double dose to make up for the dose you missed.

If you take too much Prodeinextra

If you or someone else receive too much (overdose), and experience one or more of the symptoms below, immediately call triple zero (000) for an ambulance. 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 used Prodeinextra that was prescribed for you. If someone takes an overdose they may experience one or more of the following symptoms:

  • Slow, unusual or difficult breathing
  • Drowsiness, dizziness or unconsciousness
  • Slow or weak heartbeat
  • Nausea or vomiting
  • Convulsions or fits

If you think that you have taken too much Prodeinextra, you may need urgent medical attention.

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.

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

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.

If you take too much Prodeinextra, you will probably feel nauseous, experience stomach pain, sweating, anxiety, light-headed, dizzy, or drowsy.

Depending on your body's individual ability to break down codeine, you may experience signs of overdose even when you take Prodeinextra as recommended by your doctor. If overdose symptoms occur, seek immediate medical advice.

5. What should I know while using Prodeinextra?

Things you should do

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking this medicine.

If you become pregnant while you are taking given this medicine, stop taking it and tell your doctor or pharmacist immediately.

Remind any doctor, dentist or pharmacist you visit that you are using Prodeinextra.

Things you should not do

  • Do not take more than the recommended dose unless your doctor tells you to.

Adults and children over 12 years should not take more than 8 caplets a day.

Do not take high doses of the medicine for long periods of time unless your doctor tells you to. Taking more than the recommended dose may cause liver damage. Codeine may be habit forming.

  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not use this medicine to treat any other complaints unless your doctor tells you to.

Driving or using machines

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

Prodeinextra may cause dizziness, drowsiness or light-headedness and problems with vision in some people, especially after the first dose.

Children should not ride bikes if affected and should be supervised to avoid potential harm.

Drinking alcohol

Do not drink alcohol while taking Prodeinextra.

The effects of alcohol could be made worse while taking Prodeinextra. It is not recommended that you drink alcohol while taking Prodeinextra.

Looking after your medicine

  • Store below 30°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, 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. A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.

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.

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

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal-related:
  • nausea or vomiting
  • indigestion
  • stomach pain
  • constipation
Head and neurology-related:
  • drowsiness
  • dry mouth
  • headache
  • ringing in the ears
Skin-related:
  • sweating
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Metabolism related:
  • Symptoms of rapid breathing, rapid heart rate and changes in consciousness caused by pyroglutamic acidosis (an accumulation of pyroglutamic acid due to low levels of a protein called glutathione).
Allergy-related:
  • shortness of breath
  • swelling of the face, lips, mouth or throat, which may cause difficultly in swallowing or breathing
  • skin rash, itching, hives
  • flushing of the face
Heart related:
  • fast heartbeat
Skin-related:
  • painful red areas with blisters and peeling layers of skin which may be accompanied by fever and/or chills
  • severe blisters and bleeding in the lips, eyes, mouth, nose and genitals
  • yellowing of the skin and eyes (jaundice)
Infection-related:
  • mouth ulcers, fever and sore throat
Bleeding related:
  • bleeding, bruising more easily
Head and neurology related:
  • unusual or extreme mood swings
  • dizziness, light-headedness
  • fainting
  • confusion
  • seizures
Liver related:
  • hepatitis (symptoms include loss of appetite, itching, yellowing of the skin and eyes, light coloured bowel motions, dark coloured urine)
Urinary related:
  • problems passing urine
  • dark coloured urine
Eyes related:
  • blurred vision.
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.

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 Prodeinextra contains

Active ingredient
(main ingredient)

Paracetamol and codeine phosphate hemihydrate.

Other ingredients
(inactive ingredients)		Maize starch, purified talc, pregelatinised maize starch, povidone, stearic acid, potassium sorbate, magnesium stearate and microcrystalline cellulose.
Potential allergensContains potassium sorbate.
Prodeinextra does not contain gluten, sucrose, lactose, tartrazine or any other azo dyes.

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

What Prodeinextra looks like

Prodeinextra are white to off-white capsule-shaped tablets (caplets) marked “PRO 15” and scored on one side with a plain reverse (AUST R 205550).

Prodeinextra is available in packs of 24 and 40* caplets.

*pack size not marketed.

Who distributes Prodeinextra

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113
Toll Free Number (medical information): 1800 818 806
Email: [email protected]

This leaflet was prepared in December 2021

prodeine-ccdsv5-cmiv13-03dec21

Published by MIMS January 2022

BRAND INFORMATION

Brand name

Prodeinextra

Active ingredient

Paracetamol; Codeine phosphate hemihydrate

Schedule

S4

 

1 Name of Medicine

Paracetamol and codeine phosphate hemihydrate.

2 Qualitative and Quantitative Composition

Each capsule-shaped tablet (caplet) contains paracetamol 500 mg and codeine phosphate hemihydrate 15 mg.

Excipient with known effect(s).

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

3 Pharmaceutical Form

White to off-white capsule-shaped tablets (caplets) marked "PRO 15" and scored on one side with a plain reverse.

4 Clinical Particulars

4.1 Therapeutic Indications

For the relief of acute moderate pain and fever.

4.2 Dose and Method of Administration

Adults and children over 12 years.

2 caplets every four to six hours as required (maximum 8 caplets in 24 hours).
Use in children under 12 years is contraindicated.

4.3 Contraindications

Hypersensitivity to paracetamol or codeine or other ingredients.
It must not be used in patients with known glucose-6-phosphate-dehydrogenase deficiency or severe respiratory disease, acute respiratory disease and respiratory depression, for example acute asthma, acute exacerbations of chronic obstructive pulmonary disease since codeine may exacerbate the condition.
Paracetamol should not be used in patients with a history of intolerance to the drug.
Paracetamol should not be used in patients with severe hepatocellular insufficiency.
Due to codeine's structural similarity to morphine and oxycodone, patients experiencing systemic allergy (generalised rash, shortness of breath) to these drugs should not receive codeine.
Codeine is contraindicated in patients with diarrhoea caused by poisoning, until the toxic substance has been eliminated from the gastrointestinal tract, or diarrhoea associated with pseudomembranous colitis caused by antibiotic administration since codeine may slow the elimination of the toxic material or antibiotic.
Paracetamol should not be used in patients with active alcoholism as chronic excessive alcohol ingestion predisposes patients to paracetamol hepatotoxicity.
Prodeinextra is contraindicated during breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).
Prodeinextra is contraindicated in patients younger than 12 years of age (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
Prodeinextra is contraindicated in patients aged between 12-18 years in whom respiratory function might be compromised, including post tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, due to an increased risk of developing serious and life-threatening adverse reactions (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
Prodeinextra is also contraindicated for use in patients who are CYP 2D6 ultra-rapid metabolisers (see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism).
Prodeinextra is contraindicated in the event of impending childbirth or in case of risk of premature birth.

4.4 Special Warnings and Precautions for Use

Hepatotoxicity may occur with paracetamol even at therapeutic doses, after short treatment duration and in patients without pre-existing liver dysfunction. In view of the increased risk of hepatotoxicity, the benefit should be weighed against the risk when administering Prodeinextra to patients with viral hepatitis or pre-existing hepatic disease. In such patients, hepatic function determinations may be required at periodic intervals during high dose or long-term therapy.

To avoid the risk of overdose.

Check that paracetamol is absent from the composition of other medicinal products taken concomitantly.
Codeine should be used with caution in patients with CNS depression or decreased respiratory reserve, e.g. in emphysema, kyphoscoliosis, hypoxia, hypercapnia or even severe obesity or cor pulmonale, or chronic obstructive pulmonary disease. Codeine may exacerbate respiratory impairment and CNS depression.
Codeine should be administered with caution in patients with impaired cardiac, hepatic or renal function, hypotension, benign prostatic hyperplasia, urethral stenosis, chronic colitis ulcerative, gallbladder conditions, multiple sclerosis, hypothyroidism, adrenocortical insufficiency (e.g. Addison's disease), shock, myxedema, acute alcohol intoxication or delirium tremens since codeine may exacerbate the symptoms or increase the risk of respiratory and/or CNS depression.
Codeine should be administered with great caution in patients with head injury, brain tumour or increased intracranial pressure since codeine may increase the risk of respiratory depression and further elevate intracranial pressure. In addition codeine can produce side effects such as confusion, miosis and vomiting which are important signs in following the clinical course of patients with head injuries.
Extensive use of analgesics to relieve headaches or migraines, especially at high doses, may induce headaches that must not be treated with increased doses of the drug. In such cases the analgesic should not continue to be taken without medical advice.
Monitoring after prolonged use should include blood count, liver function and renal function.
Codeine should only be used after careful risk-benefit assessment in case of:
Opioid dependence.
Chronic constipation.
Conditions with elevated intracranial pressure and head trauma. Codeine can increase the pressure of cerebrospinal fluid and may increase the respiratory depressant effect. Like other narcotics, it causes adverse reactions that can obscure the clinical course of patients with head injury.
Impaired consciousness.
Compromised respiratory function (due to emphysema, kyphoscoliosis, severe obesity) and chronic obstructive airway disease.
Patients with known analgesic intolerance or known bronchial asthma must only use Prodeinextra after having consulted a physician (hypersensitivity reactions including bronchospasm possible).
Caution is advised in patients with underlying sensitivity to aspirin and/or to nonsteroidal anti-inflammatory drugs (NSAIDs).*
* Changes of clinical significance.

Severe cutaneous adverse reactions (SCARs).

Life threatening cutaneous reactions Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported with the use of paracetamol. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. If symptoms or signs of SJS and TEN (e.g. progressive skin rash often with blisters or mucosal lesions) occur, patients should stop paracetamol treatment immediately and seek medical advice.
Paracetamol should be used upon medical advice in patients with:
mild to moderate hepatocellular insufficiency (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment); severe renal insufficiency (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment);
chronic alcohol use including recent cessation of alcohol intake;
low glutathione reserves;
Gilbert's syndrome.
Codeine should be administered with caution in patients with acute abdominal conditions since codeine may obscure the diagnosis or the course of the disease. Codeine should be administered with caution in patients with severe inflammatory bowel disease (risk of toxic megacolon may be increased, especially with repeated dosing). Prodeinextra should also be used with caution in patients who have had recent gastrointestinal tract surgery.
Patients who have had a cholecystectomy should be treated with caution. The contraction of the sphincter of Oddi can cause symptoms resembling those of myocardial infarction or intensify the symptoms in patients with pancreatitis.
Codeine should be administered with caution in patients with a history of convulsive disorders (convulsions may be induced or exacerbated by codeine).
Codeine should be administered with caution in patients with prostatic hypertrophy, urethral stricture or recent urinary tract surgery since codeine may cause urinary retention.
Codeine should be used with caution in elderly or debilitated patients because of the danger of respiratory or cardiac depression.
Codeine should be administered with caution in patients taking monoamine oxidase inhibitors (MAOIs) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

CYP2D6 metabolism.

Prodeinextra is contraindicated for use in patients who are CYP2D6 ultra-rapid metabolisers.
Codeine is metabolised by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect will not be obtained.
However, if the patient is an extensive or ultra-rapid metaboliser, there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher than expected serum morphine levels. General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation, and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life-threatening and very rarely fatal. Children are particularly susceptible due to their immature airway anatomy. Deaths have been reported in children with rapid metabolism who were given codeine for analgesia post adenotonsillectomy. Morphine can also be ingested by infants through breast milk, causing risk of respiratory depression to infants of rapid metaboliser mothers who take codeine. The prevalence of codeine ultra-rapid metabolism by CYP 2D6 in children is not known, but is assumed to be similar to that reported in adults. The prevalence of ultra-rapid metabolisers differs according to racial and ethnic group. It is estimated to be 1% in those of Chinese, Japanese and Hispanic descent, 3% in African Americans and 1%-10% in Caucasians. The highest prevalence (16%-28%) occurs in North African, Ethiopian and Arab populations. (See Section 4.4 Special Warnings and Precautions for Use, Paediatric use; Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation.)

Hazardous and harmful use.

Prodeinextra contains the opioid codeine and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Prodeine 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 Prodeinextra.
There have been reports of drug abuse with codeine, including cases in children and adolescents. Caution is particularly recommended for use in children, adolescents, young adults and in patients with a history of drug and/or alcohol abuse. See Section 4.4 Special Warnings and Precautions for Use, Paediatric use.
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 Prodeinextra 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 Prodeinextra 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, in patients with hepatic and renal impairment (see Use in hepatic impairment and Use in renal impairment) and in patients with existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma). Opioids should be used with caution and with close monitoring in these patients. 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.

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 Prodeinextra 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 Prodeinextra 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 taking Prodeinextra.

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-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.
When discontinuing Prodeinextra 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).

Accidental ingestion/exposure.

Accidental ingestion or exposure of Prodeinextra, especially by children, can result in a fatal overdose of codeine. Patients and their caregivers should be given information on safe storage and disposal of unused Prodeinextra (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. 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.

Use in hepatic impairment.

Prodeinextra should be administered with caution to patients with hepatic dysfunction, viral hepatitis, and to patients taking other drugs which affect the liver.

Use in renal impairment.

Prodeinextra should be administered with caution to patients with renal dysfunction.

Use in the elderly.

Elderly people may be more sensitive to the effects of this medicinal product, especially respiratory depression. The elderly are more likely to have hypertrophy, prostatic obstruction and age-related renal impairment and may be more susceptible to the undesirable effects due to opioid-induced urinary retention and the respiratory effects of opioid analgesics. Dose reduction may be required.

Paediatric use.

This product is contraindicated for use in children:
younger than 12 years;
aged between 12 - 18 years in whom respiratory function might be compromised, including post tonsillectomy and/or adenoidectomy for obstructive sleep apnoea. Respiratory depression and death have occurred in some children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolisers of codeine due to a CYP2D6 polymorphism.
(Also see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism.)

Effects on laboratory tests.

Plasma amylase and lipase activity.

Codeine may cause increased biliary tract pressure, thus increasing plasma amylase and/or lipase concentrations.

Gastric emptying studies.

Gastric emptying is delayed by codeine so gastric emptying studies will not be valid.

Uric acid and blood glucose.

Intake of paracetamol may affect the laboratory determination of uric acid by phosphotungstic acid and of blood glucose by glucose oxidase-peroxidase.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Salicylates and NSAIDs.

Prolonged concurrent use of paracetamol and salicylates or nonsteroidal anti-inflammatory drugs may increase the risk of adverse renal effects.

Coumarins.

Paracetamol may increase the risk of bleeding in patients taking warfarin and other antivitamin K. Patients should be monitored for appropriate coagulation and bleeding complications.

Chloramphenicol.

Paracetamol may slow down the excretion of chloramphenicol, entailing the risk of increased toxicity.

Diflunisal.

Diflunisal may increase the plasma concentrations of paracetamol by 50%.

Anticholinergics.

Concomitant use of codeine and anticholinergic agents may increase the risk of severe constipation and/or urinary retention. Drugs, which decrease gastric emptying, may decrease the absorption of paracetamol.

Cholestyramine.

Cholestyramine reduces the absorption of paracetamol if given within one hour of paracetamol administration.

Chelating resin.

Chelating resin can decrease the intestinal absorption of paracetamol and potentially decrease its efficacy if taken simultaneously. In general, there must be an interval of more than 2 hours between taking the resin and taking paracetamol, if possible.

Propantheline.

Decreases gastric emptying which may decrease the absorption of paracetamol.

Alcohol.

Codeine may potentiate the effects of alcohol. The concomitant use of alcohol and opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. Concomitant use with alcohol is not recommended (see Section 4.4 Special Warnings and Precautions for Use).

Flucloxacillin.

Coadministration of flucloxacillin with paracetamol may lead to metabolic acidosis, particularly in patients presenting risk factors of glutathione depletion, such as sepsis, malnutrition or chronic alcoholism.

Metoclopramide.

Codeine may antagonise the effects of metoclopramide on gastrointestinal motility. Paracetamol absorption is increased by drugs which increase gastric emptying.

Domperidone.

The absorption rate of paracetamol may be increased by domperidone.

Opioid analgesics.

Concurrent use of codeine and other opioid agonists is usually inappropriate as additive CNS depression, respiratory depressant and hypotensive effects may occur. Narcotic analgesics may decrease gastric emptying and therefore decrease the absorption of paracetamol.

Morphinic agonists-antagonists.

Concomitant use of codeine with a partial agonist (e.g. buprenorphine) or antagonist (e.g. naltrexone) can precipitate or delay codeine effects.

Tranquillisers, sedatives, hypnotics, general anaesthetics and CNS depressants.

Codeine may potentiate the effects of these drugs. Concomitant use of tranquillisers or sedatives may enhance the potential respiratory depressant effects of codeine. The concomitant use of benzodiazepines and opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. Limit dosage and duration of concomitant use of benzodiazepines and opioids (see Section 4.4 Special Warnings and Precautions for Use).

Hepatotoxic drugs and liver microsomal enzyme inducers.

The risk of paracetamol toxicity may be increased in patients receiving other potentially hepatotoxic drugs or drugs that induce liver microsomal enzymes, such as antiepileptics (such as phenobarbital, phenytoin, carbamazepine, topiramate), barbiturates, rifampicin and alcohol.

Zidovudine.

When used concurrently with zidovudine, an increased tendency for neutropenia or hepatotoxicity may develop. Combination of Prodeinextra and zidovudine should be avoided. If chronic paracetamol and zidovudine are to be given concurrently, monitor white blood cell count and liver function tests, especially in malnourished patients.

Antiperistaltic antidiarrhoeals (including kaolin, pectin, loperamide).

Concurrent use of these agents with codeine may increase the risk of severe constipation and CNS depression.

Monoamine oxidase inhibitors.

Nonselective MAOIs intensify the effects of opioid drugs, which can cause anxiety, confusion and significant respiratory depression and other side effects of unpredictable severity. Severe and sometimes fatal reactions have occurred in patients concurrently administered MAO inhibitors and pethidine. Codeine should not be given to patients taking nonselective MAOIs or within two weeks of stopping such treatment. As it is unknown whether there is an interaction between the selective MAOIs (reversible inhibitors of monoamine oxidase A) and codeine, caution is advised with this drug combination.

Tricyclic antidepressants.

A codeine-induced respiratory depression can be potentiated by tricyclic antidepressants.

Antihypertensives.

Hypotensive effects of antihypertensive agents may be potentiated when used concurrently with codeine and lead to orthostatic hypotension.

Neuromuscular blocking agents.

Codeine may enhance the effects of neuromuscular blocking agents resulting in increased respiratory depression.
Patients receiving other narcotic analgesics, antitussives, antihypertensives, antihistamines, antipsychotics, antianxiety agents or other CNS depressants (including gabapentinoids, cannabis, centrally-active anti-emetics, alcohol) concomitantly with this codeine-containing medicine may exhibit additive CNS depression (see Section 4.4 Special Warnings and Precautions for Use).

CYP2D6 inhibitors.

Codeine is metabolized by the liver enzyme CYP2D6 to its active metabolite morphine. Medicines that inhibit CYP2D6 activity may reduce the analgesic effect of codeine. Patients taking codeine and moderate to strong CYP2D6 inhibitors (such as quinidine, fluoxetine, paroxetine, bupropion, cinacalcet, methadone) should be adequately monitored for reduced efficacy and withdrawal signs and symptoms. If necessary, an adjustment of the treatment should be considered.

CYP3A4 inducers.

Medicines that induce CYP3A4 activity may reduce the analgesic effect of codeine. Patients taking codeine and CYP3A4 inducers (such as rifampin) should be adequately monitored for reduced efficacy and withdrawal signs and symptoms. If necessary, an adjustment of the treatment should be considered.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

See Section 5.3 Preclinical Safety Data, Carcinogenicity.
(Category A)
Paracetamol crosses the placenta, however problems in humans have not been documented. Opioid analgesics cross the placenta. Regular use during pregnancy may cause physical dependence in the foetus, leading to withdrawal symptoms in the neonate. Administration of codeine during labour may cause respiratory depression in the newborn infant. Codeine may cause respiratory depression and withdrawal syndrome in neonates born to mothers who use codeine during the third trimester of pregnancy. As a precautionary measure, use of Prodeinextra should be avoided during the third trimester of pregnancy and during labour.
 Prodeinextra is contraindicated during breastfeeding (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism) due to risk of respiratory depression in the infant. Paracetamol is excreted in breast milk but neither paracetamol nor its metabolites were detected in the urine of nursing infants after 650 mg maternal dose. If Prodeinextra is administered to a nursing mother, alternative arrangements should be made for feeding the infant.
Analgesic doses excreted in breast milk are generally low. However, infants of breastfeeding mothers taking codeine may have an increased risk of morphine overdose if the mother is an ultrarapid metaboliser of codeine. Codeine is excreted into human breast milk. Codeine is partially metabolized by cytochrome P450 2D6 (CYP2D6) into morphine, which is excreted into breast milk. If nursing mothers are CYP2D6 ultrarapid metabolisers, higher levels of morphine may be present in their breast milk. This may result in symptoms of opioid toxicity in both mother and the breastfed infant. Life threatening adverse events or neonatal death may occur even at therapeutic doses (see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism).
Therefore, Prodeinextra is contraindicated for use during breastfeeding. However, in circumstances where a breastfeeding mother requires codeine therapy, breastfeeding should be suspended and alternative arrangements should be made for feeding the infant for any period during codeine treatment. Breast feeding mothers should be told how to recognise signs of high morphine levels in themselves and their babies. For example, in a mother symptoms include extreme sleepiness and trouble caring for the baby. In the baby, symptoms include signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Medical advice should be sought immediately.

4.7 Effects on Ability to Drive and Use Machines

Prodeinextra may cause drowsiness, disturbances of visuomotor coordination and visual acuity and/or dizziness. Due to the preparation's sedative action, impairment of the mental and/or physical abilities required for the performance of potentially hazardous activities may occur. Hence children engaging in bike riding and other hazardous activities should be supervised to avoid potential harm.
Patients should not drive, operate machinery, or drink alcohol whilst taking this medication.
Source: Text updated in line with TGA request dated 14 August 2020.

4.8 Adverse Effects (Undesirable Effects)

Reports of adverse reactions are rare. Although the following reactions have been reported when paracetamol and codeine have been administered.

Haematologic.

Less frequent to rare: agranulocytosis, anaemia, thrombocytopenia.

Genitourinary.

Less frequent to rare: renal failure, uraemia, urinary retention or hesitance.

Hypersensitive.

Less frequent to rare: skin rashes and other allergic reactions, histamine release (hypotension, flushing of the face, tachycardia, breathlessness).

Gastrointestinal.

Common: constipation, nausea, vomiting.

Neurological.

Common: drowsiness, dizziness.
Less frequent to rare: euphoria, dysphoria, at higher doses codeine may cause respiratory depression.

Hepatic.

Very rare: pancreatitis.

Metabolism and nutrition system disorders.

Not known: pyroglutamic acidosis, in patients with pre-disposing factors for glutathione depletion.
Paracetamol has also been associated with dyspepsia, sweating, erythema, urticaria, anaphylactic shock, angioneurotic oedema, leukopenia, neutropenia and pancytopenia. Bronchospasms may be triggered in patients having a tendency of analgesic asthma. Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalised exanthematous pustulosis, fixed drug eruption (see Section 4.4 Special Warnings and Precautions for Use), cytolytic hepatitis, which may lead to acute hepatic failure, have also been reported.
Haemolytic anaemia in particular in patients with underlying glucose 6-phosphate dehydrogenase deficiency has been reported. Kounis syndrome and bronchospasm have also been reported.
Codeine has also been associated with confusional state, dysphoria, seizure, headache, somnolence, sedation, miosis, tinnitus, dry mouth, pruritus, fatigue, hypotension. Visuomotor coordination and visual acuity may be adversely affected in a dose-dependent manner at higher doses or in particular sensitive patients. Long term use also entails the risk of drug dependence.

Reporting suspected adverse effects.

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

4.9 Overdose

Elderly persons, small children, patients with liver disorders, chronic alcohol consumption or chronic malnutrition, as well as patients concomitantly treated with enzyme-inducing drugs are at an increased risk of intoxication, including fatal outcome.

Symptoms.

Toxic symptoms include vomiting, abdominal pain, hypotension, sweating, central stimulation with exhilaration and convulsions in children, drowsiness, respiratory depression, cyanosis and coma. Nausea, vomiting, anorexia, pallor and abdominal pain generally appear during the first 24 hours of overdosage with paracetamol. Overdosage with paracetamol may cause hepatic cytolysis which can lead to hepatocellular insufficiency, gastrointestinal bleeding, metabolic acidosis, encephalopathy, disseminated intravascular coagulation, coma and death. Increased levels of hepatic transaminases, lactate dehydrogenase and bilirubin with a reduction in prothrombin level can appear 12 to 48 hours after acute overdosage. It can also lead to pancreatitis, acute renal failure and pancytopenia. The most serious adverse effect of acute overdosage of paracetamol is a dose dependent, potentially fatal hepatic necrosis. In adults, hepatotoxicity may occur after ingestion of a single dose of 10 to 15 g (30 tablets) of paracetamol; a dose of 25 g (50 tablets) or more is potentially fatal. Symptoms during the first two days of acute poisoning by paracetamol do not reflect the potential seriousness of the intoxication. Major manifestations of liver failure such as jaundice, hypoglycaemia and metabolic acidosis may take at least three days to develop.
In an evaluation of codeine intoxication in children, symptoms seen included: sedation, rash, miosis, vomiting, itching, ataxia and swelling of the skin. Respiratory failure may occur.
The ingestion of very high doses of codeine can cause initial excitation, anxiety, insomnia followed by drowsiness in certain cases, areflexia progressing to stupor or coma, headache, miosis, alterations in blood pressure, arrhythmias, dry mouth, hypersensitivity reactions, cold clammy skin, bradycardia, tachycardia, convulsions, gastrointestinal disorders, nausea, vomiting and respiratory depression.
Severe intoxication can lead to apnoea, circulatory collapse, cardiac arrest and death.

Treatment.

Despite lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention.
Consists primarily of management of paracetamol toxicity; naloxone is the treatment of choice for codeine intoxication. In cases of overdosage, methods of reducing the absorption of ingested drug are important. Prompt administration of 50 g activated charcoal and 500 mL iced mannitol 20% by mouth may reduce absorption.
Determinations of the plasma concentration of paracetamol are recommended.
Plasma concentration of paracetamol should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable).
Where paracetamol intoxication is suspected, intravenous administration of SH group donators such as acetylcysteine within the first 10 hours after ingestion is indicated. Although acetylcysteine is most effective if initiated within this period, it can still offer some degree of protection if given as late as 48 hours after ingestion; in this case it is taken for longer.
If the history suggests that 15 g paracetamol or more has been ingested, administer one of the following antidotes.

Acetylcysteine 20% i.v.

Administer 20% acetylcysteine (Parvolex, David Bull) immediately without waiting for positive urine test or plasma level results: initial dose 150 mg/kg over 15 minutes, followed by continuous infusion of 50 mg/kg in 500 mL 5% glucose over 4 hours and 100 mg/kg in 1 L 5% glucose over 16 hours; or

Oral methionine.

2.5 g immediately followed by three further doses of 2.5 g at four hourly intervals. For a 3 year old child, 1 g methionine 4 hourly for four doses has been used.
If more than ten hours have elapsed since the overdosage was taken, the antidote may be ineffective.

Relating to codeine component.

In general, treatment should be symptomatic: re-establish adequate respiratory exchange by ensuring a clear airway and using mechanical ventilation. When treatment for paracetamol toxicity has been initiated the opioid antagonist naloxone hydrochloride is an antidote to respiratory depression; naloxone 400 microgram may be administered SC, IM or IV; IV may be repeated at intervals of 2 to 3 minutes if necessary. Assisted respiration may be required.
Further measures will depend on the severity, nature and course of clinical symptoms of intoxication and should follow standard intensive care protocols.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Analgesic and antipyretic.
Paracetamol's analgesic mechanism of action has not been fully elucidated but may involve blocking impulse generation at the bradykinin sensitive chemoreceptors, that evoke pain. The antipyretic effect of paracetamol rises from its ability to block the action of prostaglandin synthetase and so prevent the synthesis of prostaglandins in response to the pyrogen stimulus in the region of the anterior hypothalamus.
Codeine acts centrally. It produces analgesia by dulling the response to painful stimuli at several loci in the CNS. This causes an alteration in the sensation and affective response of pain.
There is evidence to suggest that a combination of paracetamol with codeine is superior in analgesic action to either drug administered alone.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration, paracetamol is absorbed rapidly and completely from the small intestine; peak plasma levels occur 30 to 120 minutes after administration. Food intake delays paracetamol absorption. Codeine has about one-sixth of morphine's analgesic activity. It is well absorbed from the gastrointestinal tract and does not interfere with paracetamol absorption.

Distribution.

Paracetamol is uniformly distributed throughout most body fluids; the apparent volume of distribution is 1 to 1.2 L/kg.
Paracetamol can cross the placenta and is excreted in milk. Plasma protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations.

Metabolism.

Paracetamol is metabolised by the hepatic microsomal enzyme system. In adults at therapeutic doses, paracetamol is mainly conjugated with glucuronide (45-55%) or sulfate (20-30%). A minor proportion (less than 20%) is metabolised to catechol derivatives, and mercapturic acid compounds via oxidation. Paracetamol is metabolised differently by infants and children compared to adults, the sulfate conjugate being predominant.
Patients who metabolise drugs poorly via CYP2D6 are likely to obtain reduced benefit from codeine due to reduced formation of the active metabolite.

Excretion.

Paracetamol is excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted as unchanged paracetamol with 85-90% of the administered dose eliminated in the urine within 24 hours of ingestion. The elimination half-life varies from 1 to 4 hours.
Codeine is metabolised in the liver to morphine and norcodeine, which with codeine, are excreted in the urine, partly as conjugates with glucuronic acid. Excretion is almost complete within 24 hours.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

Toxicity studies in animals have shown that high doses of paracetamol cause testicular atrophy and inhibition of spermatogenesis; the relevance of this finding to use in humans is not known.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each capsule-shaped tablet (caplet) contains maize starch, purified talc, pregelatinised maize starch, povidone, stearic acid, potassium sorbate, magnesium stearate and microcrystalline cellulose.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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 30°C.

6.5 Nature and Contents of Container

Available in blister packs of 6*, 12*, 20*, 24 and 40 caplets.
* Denotes presentations not available in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


Paracetamol MW: 151.17.
Codeine phosphate hemihydrate MW: 406.37.

CAS number.

Paracetamol: CAS No. 103-90-2.
Codeine phosphate hemihydrate: CAS No. 1444-62-6.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (Schedule 4).

Summary Table of Changes