Consumer medicine information

APO-Paracetamol/Codeine 500/30 Tablets

Paracetamol; Codeine phosphate hemihydrate

BRAND INFORMATION

Brand name

APO-Paracetamol/Codeine 500/30

Active ingredient

Paracetamol; Codeine phosphate hemihydrate

Schedule

What is in this leaflet

Read this leaflet carefully before taking your medicine. This leaflet answers some common questions about APO-Paracetamol/Codeine 500/30 tablets. It does not contain all the available information.

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

All medicines have risks and benefits. Your doctor has weighed the risks of you taking APO-Paracetamol/Codeine 500/30 against the benefits this medicine is expected to have for you.

Keep this leaflet with your medicine. You may want to read it again.

What this medicine is used for

APO-Paracetamol/Codeine 500/30 is used to relieve moderate to severe pain and fever.

APO-Paracetamol/Codeine 500/30 contains paracetamol and codeine. Paracetamol and codeine work together to stop the pain messages from getting through to the brain. Paracetamol also acts in the brain to reduce fever.

Your doctor may have prescribed this medicine for another use.

Ask your doctor or pharmacist if you have any questions about why the medicine has been prescribed for you.

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

Before you take this medicine

When you must not take it

Do not take this medicine :

If you are allergic to paracetamol or codeine or any of the ingredients listed under "Product Description" at the end of this leaflet.

The symptoms of an allergic reaction may include a rash, asthma attack or hay fever.

If you have or have had any of the following medical conditions:
- Acute breathing difficulties such as bronchitis, unstable asthma or emphysema
- Glucose-6-phosphate dehydrogenase deficiency (an enzyme deficiency)
- Diarrhoea caused by poisoning or antibiotics
- CYP 2D6 ultra-rapid metaboliser
If you have alcohol dependence.
During the third trimester of pregnancy.
During labour especially if the baby is premature.

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

If you are breastfeeding or planning to breastfeed.

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

In children (aged below 18 years) who have undergone tonsillectomy and/or adenoidectomy to treat obstructive sleep apnoea.
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.

If the packaging is torn or shows signs of tampering.
To treat any other complaint unless your doctor says it is safe.
APO-Paracetamol/Codeine 500/30 is not recommended for children under 12 years.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

You have allergies to:

Any other medicines
Aspirin or any other NSAID medicine
Any other substances, such as foods, preservatives or dyes
Any ingredients listed under "Product Description" at the end of this leaflet

You have or have had any medical conditions, especially the following:

Lung, liver or kidney problems
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
Diarrhoea caused by poisoning
Recent stomach, intestine or urinary tract surgery
Irritable bowel syndrome
Prostate problems
Under active thyroid gland or problems with your adrenal glands
Fits or seizures
Head injury

You are currently pregnant or you plan to become pregnant.

Your pharmacist or doctor will discuss the benefits and possible risks of taking the medicine during pregnancy.

Taking other medicines

You should also tell your doctor about any other medicines that you have bought without a prescription from either your pharmacy, supermarket or health food shop.

Tell your doctor if you are using any other medicines, including any of the following medicines:

Any medicine causing sleepiness or drowsiness
Tranquillisers (medicines for anxiety and nerves)
Medicines used to treat depression
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
Chloramphenicol (antibiotic used to treat ear and eye infections)
Rifampicin and zidovudine (medicines for infection)

These medicines may be affected by APO-Paracetamol/Codeine 500/30 or may affect how well APO-Paracetamol/Codeine 500/30 works.

Your doctor or pharmacist can tell you what to do if you are taking any of these medicines.

How to take this medicine

The label on your pack of APO-Paracetamol/Codeine 500/30 will tell you how to take your medicine and how often.

If you are unsure about the directions ask your doctor or pharmacist.

Do not take more than the dose your doctor or pharmacist has directed.

How much to take

The dosage recommended by the doctor may be different to the recommended dosage.

The recommended dose of APO-Paracetamol/Codeine 500/30 is:

Adults: 1 tablet for mild to moderate pain. 2 tablets for severe pain.

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

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.

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

If your body cannot metabolise codeine properly, you may be getting reduced benefit from the medicine.

Children (12+ years): Half (1/2) a tablet.

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

Children should not take more than 3 tablets in 24 hours.

How to take it

Swallow the tablets with water.

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 pharmacist or doctor.

If you forget to take it

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

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

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

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

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

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else has taken too much APO-Paracetamol/Codeine 500/30.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Keep telephone numbers of these places handy.

If you take too many tablets you may feel nauseous, light headed, dizzy or drowsy.

While you are taking this medicine

Things you must do

Take APO-Paracetamol/Codeine 500/30 exactly as your doctor has prescribed.

Tell all your doctors, dentists and pharmacists that you are taking APO-Paracetamol/Codeine 500/30.

Tell your doctor if you become pregnant while taking APO-Paracetamol/Codeine 500/30.

Things you must 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.

Children should not take more than 3 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 may cause liver damage.

Codeine may be habit forming.

Do not give this medicine to anyone else.

Things to be careful of

APO-Paracetamol/Codeine 500/30 may cause dizziness or drowsiness in some people, especially after the first dose.

If affected do not drive a car, operate machinery or do anything else that could be dangerous if you are dizzy or drowsy. Children should not ride bikes if affected and should be supervised to avoid potential harm.

Do not drink alcohol.

Drinking alcohol increases the likelihood of becoming drowsy.

APO-Paracetamol/Codeine 500/30 may be habit forming if taken in high doses for extended periods of time.

Ask your doctor or pharmacist if you are concerned about this.

Possible side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while taking APO-Paracetamol/Codeine 500/30.

Like other medicines, APO-Paracetamol/Codeine 500/30 can cause some side effects. If they occur, they are most likely minor and temporary. However, sometimes they are serious and need medical treatment.

If you have any questions, ask your doctor or pharmacist.

Tell your doctor if you notice any of the following.

This list includes the more common side effects. Mostly, these are mild:

Constipation
Nausea
Vomiting
Stomach pain
Dizziness
Drowsiness
Skin rashes
Sweating

Tell your doctor as soon as possible if you notice any of the following.

These may be serious side effects and you may need medical attention. Mostly, these side effects are rare:

Shortness of breath
Mouth ulcers, fever and sore throat
Bleeding, bruising more easily
Unusual or extreme mood swings
Dizziness, light-headedness
Flushing of the face
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
Hepatitis (symptoms include loss of appetite, itching, yellowing of the skin and eyes, light coloured bowel motions, dark coloured urine)

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious side effects and you may need urgent medical attention or hospitalisation. These side effects are usually very rare:

Wheezing or difficulty breathing
Swelling of the face, lips, tongue or other parts of the body
Rash, itching or hives on the skin

If you are taking APO-Paracetamol/Codeine 500/30 regularly, you may also need to take laxatives to prevent constipation.

Some people may get other side effects not listed above.

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

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

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

Disposal

If your doctor tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO- Paracetamol/Codeine 500/30 looks like

APO-Paracetamol/Codeine 500/30 tablets comes as a white, round, engraved with "PC" on one side and score line on other side.

It comes in boxes of 20 or 50 tablets.

* Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each tablet contains paracetamol 500mg and codeine phosphate Hemihydrate 30 mg as the active ingredient.

It also contains the following inactive ingredients:

Pregelatinised maize starch
Stearic acid
Povidone
Magnesium stearate

APO-Paracetamol/Codeine does not contain gluten, lactose, sucrose, tartrazine or any azo dyes.

Australian Registration Numbers

APO-Paracetamol/Codeine 500/30:
AUST R 220980

Distributor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

Apotex Pty Ltd is the licensee of the registered trademarks APO and APOTEX from the registered proprietor, Apotex Inc.

This leaflet was last updated in July 2017.

Published by MIMS April 2018

BRAND INFORMATION

Brand name

APO-Paracetamol/Codeine 500/30

Active ingredient

Paracetamol; Codeine phosphate hemihydrate

Schedule

1 Name of Medicine

Paracetamol and codeine phosphate hemihydrate.

6.7 Physicochemical Properties

Paracetamol MW 151.17. Codeine phosphate MW 406.37.

Chemical formula.

Paracetamol: C₈H₉NO₂.
Codeine phosphate: C₁₈H₂₄NO₇P,½H₂O.

Chemical name.

Paracetamol: N-(4-Hydroxyphenyl)acetamide.
Codeine phosphate: 7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate hemihydrate.
Paracetamol is a white or almost white, crystalline powder. It is sparingly soluble in water, freely soluble in alcohol and very slightly soluble in methylene chloride. It has a melting point between 168°C and 172°C.
Codeine phosphate is a white or almost white, crystalline powder or small, colourless crystals. It is freely soluble in water and slightly soluble or very slightly soluble in ethanol (96 per cent).

Chemical structure.

CAS number.

Paracetamol: CAS No. 103-90-2.
Codeine phosphate hemihydrate: CAS No. 41444-62-6.

2 Qualitative and Quantitative Composition

Each tablet contains paracetamol 500 mg and codeine phosphate hemihydrate 30 mg.
Excipients of known effect: none.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

APO-Paracetamol/Codeine 500/30 tablet is available as white, round, engraved with "PC" on one side and score line on other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Analgesic and antipyretic. 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.
Codeine is metabolised in the liver to morphine and norcodeine.

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, morphine and norcodeine 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.

4 Clinical Particulars

4.1 Therapeutic Indications

Relief of moderate to severe pain, and fever.

4.3 Contraindications

APO-Paracetamol/Codeine 500/30 must not be used in patients with known hypersensitivity to paracetamol, codeine or any of the excipients used in this product. It must not be used in patients with known glucose-6-phosphate-dehydrogenase deficiency or pre-existing 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.
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).
APO-Paracetamol/Codeine 500/30 is contraindicated during breast-feeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).
APO-Paracetamol/Codeine 500/30 is contraindicated for use in patients who are:
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).
APO-Paracetamol/Codeine 500/30 is contraindicated for use in patients who are CYP2D6 ultra-rapid metabolisers (see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism).

4.4 Special Warnings and Precautions for Use

Identified precautions.

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 APO-Paracetamol/Codeine 500/30 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.
Caution is advised in patients with underlying sensitivity to aspirin and/or to non-steroidal anti-inflammatory drugs (NSAIDs).

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.
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 and in cases of benign prostatic hyperplasia, urethral stenosis, chronic colitis ulcerative, 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 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.
Codeine should be used with caution in patients with a history of drug abuse. Prolonged use of high doses of codeine may produce dependence and/or addiction. Tolerance may also result following repeated administration.
Codeine has a primary potential for dependence. Tolerance, psychological and physical dependence with prolonged use of high doses with withdrawal symptoms after sudden discontinuation of the drug. Cross-tolerance with other opioids exists. Rapid relapses can be expected in patients with pre- existing opiate dependence (including those in remission).
Administration must be discontinued gradually after prolonged treatments.
Monitoring after prolonged use should include blood count, liver function and renal function.
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).
Codeine should only be used with careful risk-benefit assessment and great caution in case of the following.
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 APO-Paracetamol/Codeine 500/30 after having consulted a physician (hypersensitivity reactions including bronchospasm possible).
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). APO-Paracetamol/Codeine 500/30 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 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 structure 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).

Risk from concomitant use of opioids and benzodiazepines.

Concomitant use of opioids, including codeine, with benzodiazepines may result in sedation, respiratory depression, coma and death. Because of these risks, reserve concomitant prescribing of opioids and benzodiazepines for use in patients for whom alternative treatment options are inadequate.
If a decision is made to prescribe codeine concomitantly with benzodiazepines, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of sedation and respiratory depression (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Patients should be advised to first consult their healthcare professional before taking codeine if they are taking a benzodiazepine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Risks from concomitant use of opioids and alcohol.

Concomitant use of opioids, including codeine, with alcohol may result in sedation, respiratory depression, coma and death. Concomitant use with alcohol is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

CYP2D6 metabolism.

APO-Paracetamol/Codeine 500/30 is contraindicated for use in patients who are CYP2D6 ultra-rapid metabolisers.
Codeine is metabolized 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 metabolizer 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 metabolizer 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 ultra-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.)

Use in hepatic impairment.

APO-Paracetamol/Codeine 500/30 should be administered with caution to patients with hepatic or renal dysfunction, viral hepatitis, and to patients taking other drugs, which affect the liver.

Use in renal impairment.

APO-Paracetamol/Codeine 500/30 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. 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.

APO-Paracetamol/Codeine 500/30 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.

Coumarins.

Paracetamol may increase the risk of bleeding in patients taking warfarin and other coumarin derivatives (antivitamin K). Monitoring of coagulation and bleeding complications is required.

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.

Propantheline.

Decreases gastric emptying which may decrease the absorption of paracetamol.

Rifampicin.

Concomitant use may increase the likelihood of paracetamol toxicity (see Hepatotoxic drugs and liver microsomal enzymes below).

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.

Alcohol.

Codeine may potentiate the effects of alcohol and increase the likelihood of paracetamol toxicity (see Hepatotoxic drugs and liver microsomal enzymes below). 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).

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 agonist-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.

Benzodiazepines.

The concomitant use of alcohol and opioids increases the risk of sedation, respiratory depression, coma and death because 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.

Zidovudine.

When used concurrently with zidovudine, an increased tendency for neutropenia or hepatotoxicity may develop. Combination of APO-Paracetamol/Codeine 500/30 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.

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.

Non-selective MAOI's 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 non-selective MAOI's or within 2 weeks of stopping such treatment. As it is unknown whether there is an interaction between the selective MAOI's (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 antidepressant.

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 alcohol) concomitantly with paracetamol/codeine 500/30 may experience additive CNS depression.

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 APO-Paracetamol/Codeine 500/30 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). Paracetamol/codeine 500/30 should only be used during pregnancy under medical supervision if the potential benefit justifies the potential risk to the foetus. If administered during pregnancy, morphinomimetic properties of codeine should be taken into account.
APO-Paracetamol/Codeine 500/30 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 breast feeding 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 breast-fed 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, APO-Paracetamol/Codeine 500/30 is contraindicated for use during breastfeeding. However, in circumstances where a breastfeeding mother required 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.

4.8 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.
Paracetamol has also been associated with dyspepsia, sweating, erythema, urticarial, 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 and cytolytic hepatitis, which may lead to acute hepatic failure, have also been reported.
Haemolytic anaemia particularly 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. 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.

4.2 Dose and Method of Administration

Adults.

The initial dose is 1 tablet, repeated every 4 to 6 hours if necessary for mild to moderate pain. The initial dose is 2 tablets repeated every 4 to 6 hours if necessary (maximum 8 tablets per day) for severe pain.
APO-Paracetamol/Codeine 500/30 is contraindicated for use in patients who are:
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. (Also see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use.)
Tablets to be taken with water.

4.7 Effects on Ability to Drive and Use Machines

APO-Paracetamol/Codeine 500/30 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 treated with this medication should not drive, operate machinery, or drink alcohol whilst taking this medication.

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.
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.
In general, treatment for codeine overdose should be symptomatic: re-establish adequate respiratory exchange by ensuring a clear airways and using mechanical ventilation. When treatment for paracetamol toxicity has been initiated; 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 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Other ingredients are: pregelatinised maize starch, stearic acid, povidone, magnesium stearate.

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 25°C.

6.5 Nature and Contents of Container

APO-Paracetamol/Codeine 500/30 is available in cartons of 2*, 4*, 10*, 20 and 50* round tablets packaged in PVC/Aluminium foil blisters.
*Non-marketed pack sizes.

6.6 Special Precautions for Disposal

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

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