Consumer medicine information

Codalgin Forte

Paracetamol; Codeine phosphate hemihydrate

BRAND INFORMATION

Brand name

Codalgin Forte

Active ingredient

Paracetamol; Codeine phosphate hemihydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Codalgin Forte.

SUMMARY CMI

CODALGIN® FORTE

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 CODALGIN FORTE?

CODALGIN FORTE contains the active ingredients paracetamol and codeine phosphate hemihydrate. CODALGIN FORTE is used for the short-term management of severe pain when all other pain management options have not worked.

For more information, see Section 1. Why am I using CODALGIN FORTE? in the full CMI.

2. What should I know before I use CODALGIN FORTE?

Do not use if you have ever had an allergic reaction to CODALGIN FORTE 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.

You may develop addiction, dependence, and tolerance. For more information, see Section 2. What should I know before I use CODALGIN FORTE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with CODALGIN FORTE 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 use CODALGIN FORTE?

The standard dose for adults is 1 or 2 tablets for severe pain, taken every 4 to 6 hours if necessary. More instructions can be found in Section 4. How do I use CODALGIN FORTE? in the full CMI.

5. What should I know while using CODALGIN FORTE?

Things you should doRemind any doctor, dentist or pharmacist you visit that you are using CODALGIN FORTE. Talk to your doctor about pain control if the medicine is not helping. Tell your doctor if you become pregnant while taking CODALGIN FORTE.
Things you should not doDo 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 CODALGIN FORTE to children under 12. Do not take high doses of the medicine for long periods of time, unless your doctor tells you to.
Driving or using machinesBe careful before you drive or use any machines or tools until you know how CODALGIN FORTE affects you. CODALGIN FORTE may cause dizziness, drowsiness, or light-headedness in some people, especially after the first dose.
Drinking alcoholDo not drink alcohol while taking CODALGIN FORTE.
Looking after your medicineStore below 30°C. Keep medicines where children cannot reach them. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

For more information, see Section 5. What should I know while using CODALGIN FORTE? 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 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

CODALGIN FORTE should only be used when your doctor decides that other treatment options are not able to effectively manage your pain, or you cannot tolerate them.

Hazardous and Harmful Use

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

Life Threatening Respiratory Depression

CODALGIN FORTE can cause life-threatening or fatal breathing problems (slow, shallow, unusual or no breathing), even when used as recommended. These problems can occur at any time during use, but the risk is higher when first starting CODALGIN FORTE 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 CODALGIN FORTE

Using CODALGIN FORTE 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 minimise the dose and duration of use; and monitor you for signs and symptoms of breathing difficulties and sedation. You must not drink alcohol while using CODALGIN FORTE.



FULL CMI

CODALGIN® FORTE

Active ingredients: paracetamol and codeine phosphate hemihydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using CODALGIN FORTE. 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 CODALGIN FORTE.

Where to find information in this leaflet:

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

1. Why am I using CODALGIN FORTE?

CODALGIN FORTE contains the active ingredients paracetamol and codeine phosphate hemihydrate. CODALGIN FORTE is an analgesic. Paracetamol and codeine phosphate hemihydrate work together to stop the pain messages from getting through to the brain. Your doctor may have prescribed this medicine for another use.

CODALGIN FORTE is used to relieve severe pain for which other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain.

2. What should I know before I use CODALGIN FORTE?

Warnings

Do not use CODALGIN FORTE 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 acute breathing difficulties such as bronchitis, unstable asthma or emphysema
  • you have Glucose-6-phosphatedehydrogenase deficiency (an enzyme deficiency)
  • you are a CYP 2D6 ultra-rapid metaboliser (a fast metaboliser of codeine by the CYP 2D6 enzyme)
  • you have diarrhoea caused by antibiotics or poisoning
  • you have liver failure

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

Do not take CODALGIN FORTE if you have experienced systemic allergy (generalised rash or shortness of breath) to morphine or oxycodone.

Do not take CODALGIN FORTE if you have a history of intolerance to paracetamol and/or codeine.

Do not take CODALGIN FORTE if you are under 18 years of age and have had your tonsils or adenoids removed to treat sleep apnoea.

Do not take CODALGIN FORTE during the third trimester of pregnancy.

Do not take CODALGIN FORTE during labour especially if the baby is premature.

Do not use CODALGIN FORTE if you are breastfeeding or planning to breastfeed.

Do not take this medicine after the expiry date (EXP) printed on the pack. If you take it after the expiry date it may have no effect at all, or worse, have an entirely unexpected effect.

Do not take this medicine if the packaging is torn or shows signs of tampering.

Do not use this medicine to treat any other complaint unless your doctor says it is safe.

CODALGIN FORTE is not recommended for children under 12 years.

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

  • low blood pressure
  • difficulty breathing, wheezing, chronic cough, asthma, or other chronic breathing conditions
  • a history of drug dependence, including alcohol
  • dependence
  • you drink large quantities of alcohol
  • recent cessation of alcohol intake
  • low glutathione reserves
  • Gilbert's syndrome
  • gall bladder problems or your gall bladder has been removed
  • multiple sclerosis
  • recent stomach, intestine or urinary tract surgery
  • irritable bowel syndrome or other bowel problems
  • prostate problems
  • under active thyroid gland or problems with your adrenal glands
  • fits or seizures
  • head injury
  • brain tumours

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

Pregnancy and breastfeeding

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

Do not take CODALGIN FORTE during the third trimester of pregnancy.

Do not take CODALGIN FORTE during labour, especially if the baby is premature.

This medicine can cause breathing problems and may produce withdrawal effects in the newborn baby.

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

The medicine passes into breast milk and may affect the baby.

Addiction

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

Tolerance

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

3. What if I am taking other medicines?

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

Some medicines may interfere with CODALGIN FORTE and affect how it works.

These include:

  • any medicine causing sleepiness or drowsiness
  • tranquillisers (medicines for anxiety and nerves)
  • benzodiazepines (medicines used as sedatives or to treat anxiety)
  • medicines used to treat alcohol and/or opioid dependence (e.g. naltrexone, buprenorphine or methadone)
  • medicines containing alcohol (ethanol), e.g. some cough syrups
  • cough suppressants or antitussives
  • antihistamines (medicines used to treat allergies)
  • medicines used to treat depression
  • medicines used to treat mental illness
  • monoamine oxidase inhibitors (medicines used to treat depression) taken within the last 10 days
  • salicylates or non-steroidal anti-inflammatory 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 drug used to treat stomach ulcers
  • cholestyramine (medicine used to treat bile problems and/or high cholesterol
  • chelating resin
  • chloramphenicol (antibiotic 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

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

4. How do I use CODALGIN FORTE?

How much to take

  • The recommended dose of CODALGIN FORTE is: Adults: 1 or 2 tablets for severe pain.

This dosage may be repeated in 4-6 hours if necessary.

  • Follow the instructions provided.

Do not take more than 8 tablets in 24 hours.

Do not take more than the recommended dose. Taking more than the recommended dose may cause liver damage.

The directions given to you by your doctor or pharmacist may be different from the information in this leaflet. If you are unsure what dose to take, ask your doctor or pharmacist.

Talk to your doctor about pain control if the medicine is not helping.

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

How to take CODALGIN FORTE

  • Swallow the tablets with water.

How long to take it for

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

If you forget to take CODALGIN FORTE

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.

This may increase the chance of you getting an unwanted side effect.

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

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

If you take too much CODALGIN FORTE

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 CODALGIN FORTE 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 used too much CODALGIN FORTE, 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.

5. What should I know while using CODALGIN FORTE?

Things you should do

Take CODALGIN FORTE exactly as your doctor has prescribed.

Tell your doctor if you become pregnant while taking CODALGIN FORTE.

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

Things you should not do

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

Adults should not take more than 8 tablets 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 can cause liver damage.

CODALGIN FORTE may be habit forming if taken in high doses for extended periods of time.

  • Do not give this medicine to anyone else.

Driving or using machines

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

CODALGIN FORTE may cause dizziness, light-headedness, drowsiness 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 CODALGIN FORTE.

Drinking alcohol increases the likelihood of becoming drowsy.

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

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.

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
  • constipation
  • stomach pain
Head and neurology related
  • dry mouth
  • drowsiness or sleepiness
  • 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
Allergy related
  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • skin rash, itching or hives on the skin
  • flushing of the face
Heart related
  • fast heartbeat
Skin related
  • severe blisters and bleeding in the lips, eyes, mouth, nose and genitals
  • painful red areas with blisters and peeling layers of skin which may be accompanied by fever and/or chills
  • 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
  • dizziness, light-headedness
  • unusual or extreme mood swings
  • 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
Metabolism related:
  • Symptoms of rapid breathing, rapid heard rate and changes in consciousness caused by pyroglutamic acidosis (an accumulation of pyroglutamic acid due to low levels of a protein called glutathione)
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 CODALGIN FORTE contains

Active ingredients
(main ingredient)		Paracetamol
Codeine phosphate hemihydrate
Other ingredients
(inactive ingredients)		Colloidal anhydrous silica
Crospovidone
Magnesium stearate
Maize starch
Microcrystalline cellulose
Povidone
Pregelatinised maize starch
Stearic acid

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

What CODALGIN FORTE looks like

CODALGIN FORTE is a white, capsule shaped tablet, plain on one side and with a break bar on the other side

It comes in boxes of 20 tablets.

Who distributes CODALGIN FORTE

Alphapharm Pty Ltd trading as Viatris
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared in July 2023.

Australian Registration Numbers:
AUST R - 226337

CODALGIN® is a Viatris company trade mark

CODALGIN-FORTE_cmi\Jul23/00

Published by MIMS September 2023

BRAND INFORMATION

Brand name

Codalgin Forte

Active ingredient

Paracetamol; Codeine phosphate hemihydrate

Schedule

S4

 

1 Name of Medicine

Paracetamol and codeine phosphate hemihydrate.

2 Qualitative and Quantitative Composition

Each Codalgin Forte tablet contains 500 mg of paracetamol and 30 mg of codeine phosphate hemihydrate as the active ingredients.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

A 16.8 mm x 7.7 mm white, capsule-shaped tablet, plain on one side and with a breakbar on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Codalgin Forte is indicated for 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.

4.2 Dose and Method of Administration

Adults and children 12 years of age and over.

1 or 2 tablets every 4 to 6 hours if necessary for relief of severe pain. Do not exceed 8 tablets in a 24-hour period.

Children under 12 years of age.

See Section 4.3 Contraindications.
Tablets to be taken with water.

4.3 Contraindications

Paracetamol should not be used in patients with active alcoholism as chronic excessive alcohol ingestion predisposes patients to paracetamol hepatotoxicity.
Paracetamol should not be used in patients with a history of intolerance or hypersensitivity to the drug.
Codalgin Forte must not be used in patients with known glucose-6-phosphate dehydrogenase deficiency or severe respiratory disease, acute respiratory disease (e.g. acute asthma, acute exacerbations of chronic obstructive pulmonary disease) and respiratory depression, since codeine may exacerbate the condition.
Codalgin Forte should not be used in patients with a history of allergic reactions to codeine.
Hypersensitivity to any of the tablet excipients.
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.
Codeine is contraindicated in the event of impending childbirth or in case of risk of premature birth (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Codalgin Forte is contraindicated for use in patients who are:
CYP2D6 ultra-rapid metabolisers (see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism);
younger than 12 years (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use);
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);
breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).

4.4 Special Warnings and Precautions for Use

Hazardous and harmful use.

Codalgin Forte contains the opioid codeine phosphate hemihydrate and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Codalgin Forte 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 Codalgin Forte.
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 Codalgin Forte 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 Codalgin Forte 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 Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment, 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 (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, (see Section 4.2 Dose and Method of Administration), 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 Codalgin Forte 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 Codalgin Forte 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 Codalgin Forte.

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 Codalgin Forte 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 Codalgin Forte, especially by children, can result in a fatal overdose of codeine phosphate hemihydrate. Patients and their caregivers should be given information on safe storage and disposal of unused Codalgin Forte (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.

CYP2D6 metabolism.

Codalgin Forte 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 CYP2D6 in children is not known, but is assumed to be similar to that reported in adults. The prevalence of ultrarapid metabolisers 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.
(Also see Section 4.4 Special Warnings and Precautions for Use, Paediatric use; Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation.)

Other information.

Codeine should be used with caution in patients with recent gastrointestinal tract surgery.
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).
Patients with known analgesic intolerance or known bronchial asthma must only use Codalgin Forte after having consulted their doctor, given the possibility of hypersensitivity reactions including bronchospasm.
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.
Codeine should be administered with great caution in patients with decreased respiratory reserve (e.g. in emphysema, kyphoscoliosis, hypoxia, hypercapnia or even severe obesity) or cor pulmonale, or chronic obstructive pulmonary disease since codeine may exacerbate respiratory impairment. Codeine should be administered with caution in patients with impaired cardiac, hepatic or renal function, hypotension, benign prostatic hyperplasia, urethral stenosis, chronic ulcerative colitis, gall bladder 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 caution in patients taking monoamine oxidase inhibitors (MAOIs), see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
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.
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 Codalgin Forte 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.

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 with caution in patients with: recent cessation of alcohol intake; low glutathione reserves; Gilbert's syndrome.
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.
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.
Caution is advised in patients with underlying sensitivity to aspirin and/or to non-steroidal anti-inflammatory drugs (NSAIDs).

Use in hepatic impairment.

Codalgin Forte should be given with care to patients with impaired hepatic function, viral hepatitis, and to patients taking other drugs which affect the liver.

Use in renal impairment.

Codalgin Forte should be given with care to patients with impaired renal function.

Use in the elderly.

Elderly people may be more sensitive to the effects of this medicinal product. The elderly are more likely to have age related renal impairment and may be more susceptible to the respiratory effects of opioid analgesics. Dose reduction may be required.
Codeine should be used with caution in elderly or debilitated patients because of the danger of respiratory or cardiac depression.

Paediatric use.

Codalgin Forte 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 non-steroidal anti-inflammatory drugs may increase the risk of adverse renal effects.

Diflunisal.

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

General anaesthetics.

Codeine may potentiate the effects of general anaesthetics.

Tranquillisers, sedatives and hypnotics.

Codeine may potentiate the effects of these drugs. Concomitant use of tranquillisers or sedatives may enhance the potential respiratory depressant effects of codeine (see Section 4.4 Special Warnings and Precautions for Use).

CNS depressants.

Codeine may potentiate the effects of CNS depressants.
Patients receiving other narcotic analgesics, antitussives, antihypertensives, antihistamines, antipsychotics, antianxiety agents, gabapentinoids, cannabis and centrally-active anti-emetics or other CNS depressants (including alcohol) concomitantly with paracetamol/codeine 500/30 may experience addictive CNS depression (see Section 4.4 Special Warnings and Precautions for Use).

Alcohol.

Codeine may potentiate the effects of alcohol and the likelihood of paracetamol toxicity may be increased by its concomitant use. 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).

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.

Anticholinergics.

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

Monoamine oxidase inhibitors.

Non-selective MAOIs intensify the effects of opioid drugs which can cause anxiety, confusion and significant respiratory depression. Severe and sometimes fatal reactions have occurred in patients concurrently administered MAO inhibitors and pethidine. Codeine should not be given to patients taking non-selective MAOIs or within 14 days 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.

Barbiturates and antiepileptic medications.

The likelihood of toxicity may be increased by the concomitant use of enzyme inducing agents such as alcohol, barbiturates or antiepileptic drugs.

Coumarins.

Repeated high doses of paracetamol increase the risk of bleeding in patients taking warfarin and other coumarin derivatives. Monitoring of coagulation and bleeding complications is required.

Chloramphenicol.

Paracetamol may also increase chloramphenicol concentrations by slowing down the excretion of chloramphenicol, thereby increasing the risk of toxicity.

Antihypertensives.

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

Antiperistaltic antidiarrhoeals (including kaolin, pectin, loperamide).

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

Metoclopramide.

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

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, gabapentinoids, cannabis and centrally-active anti-emetics or other CNS depressants (including alcohol) concomitantly with Codalgin Forte may experience additive CNS depression. (See Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol.)

Cholestyramine.

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

Rifampicin.

Concomitant use may increase the likelihood of paracetamol toxicity.

Zidovudine.

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

Chelating resin.

Chelating resin can decrease the intestinal absorption of paracetamol and potentially decrease its efficacy if taken simultaneously.

Flucloxacillin.

Co-administration 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.

Domperidone.

The absorption rate of paracetamol may be increased by domperidone.

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.

Benzodiazepines.

The concomitant use of alcohol 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), alcohol, barbiturates and rifampicin. The induced metabolism results in an elevated production of the hepatotoxic oxidative metabolite of paracetamol. Hepatotoxicity will occur if this metabolite exceeds the normal glutathione binding capacity.

Tricyclic antidepressants.

A codeine-induced respiratory depression can be potentiated by tricyclic antidepressants. (See Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol.)

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 fetus, 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 Codalgin Forte should be avoided during the third trimester of pregnancy and during labour.
Codeine is contraindicated in the event of impending childbirth or in case of risk of premature birth (see Section 4.3 Contraindications). Codalgin Forte should only be used during pregnancy under medical supervision if the potential benefit justifies the potential risk to the fetus. If administered during pregnancy, morphinomimetic properties of codeine should be taken into account.
 Codalgin Forte is contraindicated during breastfeeding (see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism) due to risk of respiratory depression in 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 ultra-rapid 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 ultra-rapid 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, Codalgin Forte 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. Breastfeeding 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

Codalgin Forte 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. Children should be supervised during bike riding or other potentially hazardous activities.
Patients treated with this medication should not drive, operate machinery, or drink alcohol whilst taking this medication.

4.8 Adverse Effects (Undesirable Effects)

Adverse effects of Codalgin Forte are generally infrequent and include:

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, anaphylactic shock, angioneurotic oedema, leukopenia 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 and 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 can cause 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

Overdosage with Codalgin Forte tablets involves treatment of both paracetamol and codeine poisoning.

Paracetamol.

Symptoms.

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. Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Increased levels of hepatic transaminases, lactate dehydrogenase and bilirubin with a reduction in prothrombin level may become apparent 12 to 48 hours after acute overdosage. Major manifestations of liver failure such as jaundice, hypoglycaemia and metabolic acidosis may take at least three days to develop. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may proceed to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop in the absence of severe liver damage. Cardiac arrhythmias have been reported. Liver damage is likely in adults who have taken 10 g or more of paracetamol, due to excess quantities of a toxic metabolite becoming irreversibly bound to liver tissue.

Treatment.

Prompt treatment is essential in the management of paracetamol overdosage even when there are no obvious symptoms and should not be delayed while waiting for laboratory results. Specific therapy with an antidote such as acetylcysteine (intravenous) or methionine (oral) should be instituted as soon as possible.
Acetylcysteine is most effective when administered during the first 8 hours following ingestion of the overdose and the effect diminishes progressively between 8 and 16 hours. It used to be believed that starting treatment more than 15 hours after overdosage was of no benefit and might possibly aggravate the risk of hepatic encephalopathy. However, late administration has now been shown to be safe and studies of patients treated up to 36 hours after ingestion suggest that beneficial results may be obtained beyond 15 hours. Furthermore, administration of intravenous acetylcysteine to patients who have already developed fulminant hepatic failure has been shown to reduce morbidity and mortality.
An initial dose of 150 mg/kg of acetylcysteine in 200 mL 5% glucose is given intravenously over 15 minutes, followed by an I.V. infusion of 50 mg/kg in 500 mL 5% glucose over 4 hours and then 100 mg/kg in 1 L 5% glucose over 16 hours. The volume of I.V. fluids should be modified for children.
Methionine is given orally as 2.5 g every 4 hours up to 10 g. Methionine treatment must be started within 10 hours after ingestion of paracetamol, otherwise it will be ineffective and may exacerbate liver damage. For a 3 year old child, 1 g methionine 4 hourly for four doses has been used.
Evidence of serious symptoms may not become apparent until 4 or 5 days following overdosage and patients should be carefully observed for an extended period.

Codeine.

Symptoms.

Symptoms of codeine overdosage include vomiting, hypotension, sweating, central stimulation with exhilaration and convulsions in children, drowsiness, respiratory depression, cyanosis, miosis and coma.
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.

Treatment.

The first step should be to establish adequate respiratory exchange by provision of a patent airway and controlled or assisted ventilation.
Naloxone is the treatment of choice and the usual adult dose is 0.4-2.0 mg repeated every 2 to 3 minutes if necessary. If no response is observed after 10 mg is administered, the diagnosis of opioid-induced toxicity should be questioned.
Children may receive an initial dose of 0.01 mg; if this dose does not produce the desired degree of response, a subsequent dose of 0.1 mg/kg may be administered.
Intravenous administration is the preferred route for naloxone, this achieves the most rapid onset of action and is recommended in emergency situations.
Since the duration of action of codeine may be longer than that of naloxone, the patient should be under surveillance, and doses of naloxone repeated as needed.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Paracetamol has analgesic and antipyretic activity similar to aspirin. The analgesic effect of paracetamol is thought to be due to inhibition of prostaglandin synthesis in the central nervous system and in the periphery, and, to a lesser extent, by blocking pain impulse generation in the periphery. The antipyretic effect is due to a central action on the hypothalamic heat regulating centre to produce peripheral vasodilatation and subsequent heat loss.
Codeine phosphate hemihydrate is an opioid analgesic that binds with stereospecific receptors at many sites within the CNS to alter processes affecting both the perceptions of pain and the emotional response to pain. There are multiple sub-types of opioid receptors, each mediating various therapeutic and/or side effects of drugs. Its analgesic effect is thought to be due to its partial metabolic conversion to morphine. Codeine has about one-sixth the analgesic activity of morphine. Codeine can also cause other effects e.g. CNS depression, nausea and vomiting, orthostatic hypotension and constipation.
It has been shown that the analgesic effects of paracetamol and codeine are additive due to their different mechanisms of action.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Paracetamol is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring some 30 minutes to 2 hours after ingestion. The onset of therapeutic action is 30 minutes and the duration of effect is 4 hours.
Codeine is well absorbed from the gastrointestinal tract and peak plasma concentrations are reached one hour after oral administration. Onset of action occurs in 15-30 minutes and analgesia is maintained for 4-6 hours.

Distribution.

Paracetamol is rapidly and uniformly distributed into most body tissues. It crosses the placenta and is present in breast milk.
Codeine is rapidly distributed to skeletal muscle, kidneys, liver, gastrointestinal tract, lungs, spleen and brain. It crosses the placenta and is distributed in low levels in breast milk.

Metabolism.

Approximately 90-95% of the paracetamol dose is metabolised in the liver, primarily by conjugation with glucuronic acid, sulphuric acid and cysteine. An intermediate metabolite which may accumulate in overdosage is hepatotoxic and possibly nephrotoxic.
Codeine is metabolised mainly in the liver. The major metabolic pathway involves glucuronidation of codeine to codeine-6-glucuronide. Codeine can also undergo O- and N-demethylation catalysed by CYP2D6 and CYP3A4 respectively. Patients who metabolise drugs poorly via CYP2D6 are likely to obtain reduced benefit from codeine due to reduced formation of the active metabolite. About 10% of an administered dose of codeine is converted by O-demethylation to morphine which subsequently undergoes glucuronidation to morphine-3 or morphine-6 glucuronide, or N-demethylation to normorphine. Approximately 5-10% of the Caucasian population cannot convert codeine to morphine as they are deficient in the CYP2D6 enzyme. Codeine is also converted by N-demethylation to norcodeine which subsequently undergoes glucuronidation to norcodeine glucuronide or O-demethylation to normorphine.

Excretion.

Approximately 85% of a dose of paracetamol is recovered from the urine within 24 hours after ingestion. About 5% is unchanged, the balance consisting mainly of the glucuronide and sulfate conjugates. The elimination half-life varies from 1 to 4 hours and may be prolonged in acute overdosage, in liver disease, the elderly and the neonate.
Codeine is excreted mainly by the kidneys as its metabolite codeine-6-glucuronide. 5-25% is excreted unchanged and approximately 10% is excreted as unchanged or conjugated morphine. The plasma half-life of codeine is 2-4 hours. Only traces of codeine and its metabolites are found in the faeces.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

Clinical 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

Maize starch, pregelatinised maize starch, povidone, microcrystalline cellulose, magnesium stearate, crospovidone, stearic acid and colloidal anhydrous silica.

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 Codalgin Forte tablets below 30°C in a dry place.

6.5 Nature and Contents of Container

Container type: blister pack (PVC/PVDC/Al).
Pack size: 4, 10, 12 and 20 tablets.
Some strengths, pack sizes and/or pack types may not be marketed.

Australian Register of Therapeutic Goods (ARTG).

AUST R 226337 - Codalgin Forte codeine phosphate hemihydrate 30 mg and paracetamol 500 mg tablet blister pack.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

Paracetamol is N-(4-Hydroxyphenyl) acetamide. It has the following chemical structure:
Molecular formula: C8H9NO2. Molecular weight: 151.2.
Paracetamol is a white colourless crystalline powder. It is sparingly soluble in water; soluble 1 in 20 of boiling water, and 1 in 10 of alcohol; very slightly soluble in ether and in methylene chloride. Store in airtight containers. Protect from light.
Codeine phosphate hemihydrate is (5R,6S)-7,8-didehydro-4,5-epoxy-3-methoxy-N-methylmorphinan-6-ol dihydrogen orthophosphate hemihydrate. It has the following chemical structure:
Molecular formula: C18H21NO3.H3PO4.½H2O. Molecular weight: 406.40.
Codeine phosphate is soluble in 4 parts of water, slightly soluble in ethanol (96%), practically insoluble in chloroform and ether.

CAS number.

Paracetamol: 103-90-2.
Codeine phosphate hemihydrate: 41444-62-6.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes