SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Codis 500

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Active Ingredients    mg/Tablet    Specification

Aspirin    500.0    Ph Eur

Codeine phosphate*    8.0    Ph Eur

*Equivalent to 6.2mg codeine

3    PHARMACEUTICAL FORM

Dispersible tablet

4.1    Therapeutic indications

Codis 500 (which contains codeine) is indicated in children older than 16 for the short term treatment of acute, moderate pain which is not considered to be relieved by other analgesics such as paracetamol, ibuprofen or aspirin alone, such as headache, muscular aches, rheumatic pain, toothache, period pains) or acute, moderate pain associated with migraine, neuralgia, sprains, strains, sciatica, lumbago, fibrositis, and joint swelling.

4.2    Posology and method of administration

For oral administration, after dissolution in water.

Codeine should be used at the lowest effective dose for the shortest period of time.

Adults:

One to two tablets or as directed, dissolved in water. The dose may be repeated after 4 hours: maximum eight tablets in 24 hours in divided doses.

Children aged 16-18 years:

One to two tablets or as directed, dissolved in water. The dose may be repeated after 4 hours: maximum eight tablets in 24 hours in divided doses.

Children aged less than 16 years:

Do not give to children aged under 16 years unless specifically indicated (e.g. Kawasaki’s disease).

Codeine should not be used in children below the age of 12 years because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see sections 4.3 and 4.4).

There is no indication that dosage needs to be modified for the elderly.

Not to be taken more frequently than every 4 hours.

The duration of treatment should be limited to 3 days and if no effective pain relief is achieved the patients/carers should be advised to seek the views of a physician.

4.3 Contraindications

Not to be given to patients with known allergy to aspirin, suffering from peptic ulceration or haemophilia.

Not to be used in all paediatric patients (0-18 years of age) who undergo tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome due to an increased risk of developing serious and life-threatening adverse reactions (see section 4.4)

Not to be used in women during breastfeeding (see section 4.6)

Not to be used in patients for whom it is known they are CYP2D6 ultra-rapid metabolisers

4.4 Special warnings and precautions for use

There is a possible association between aspirin and Reye’s Syndrome when given to children. Reye’s Syndrome is a very rarer disease which affects the brain and liver and can be fatal. For this reason aspirin should not be given to children aged under 16 years unless specifically indicated (e.g, for Kawasaki’s disease). If you are receiving regular medical treatment, are asthmatic, allergic to aspirin or have or have had a stomach ulcer, seek your doctor’s advice before taking this product.

CYP2D6 metabolism

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.

Estimates indicate that up to 7% of the caucasian population may have this deficiency. 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.

Estimates of prevalence of ultra-rapid metabolisers in different populations are summarized below:

Population	Prevalence %
African/Ethiopian	29%
African American	3.4% to 6.5%
Asian	1.2% to 2%
Caucasian	3.6% to 6.5%
Greek	6.0%
Hungarian	1.9%
Northern European	1%-2%

Post-operative use in children

There have been reports in the published literature that codeine given postoperatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life-threatening adverse events including death (see also section 4.3). All children received doses of codeine that were within the appropriate dose range; however there was evidence that these children were either ultrarapid or extensive metabolisers in their ability to metabolise codeine to morphine.

Children with compromised respiratory function

Codeine is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of morphine toxicity.

The label will include:

Front of pack:

•    Can cause addiction

•    For three days use only Back of pack:

•    For the short term treatment of acute moderate pain when other painkillers have not worked. Do not take less than four hours after taking other painkillers

•    If you need to take this medicine continuously for more than three days you should see your doctor or pharmacist

•    This medicine contains codeine which can cause addiction if you take it continuously for more than three days. If you take this medicine for headaches for more than three days it can make them worse

The labeling on packs intended for public sale will also include the statement “Do not give to children aged under 16 years unless on the advice of a doctor”.

The leaflet will include:

• Headlines section (to be prominently displayed at the start of the PIL)

•    For the short term treatment of acute, moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone

•    You should only take this product for a maximum of three days at a time. If you need to take it for longer than three days you should see your doctor or pharmacist for advice

•    This medicine contains codeine which can cause addiction if you take it continuously for more than three days. This can give you withdrawal symptoms from the medicine when you stop taking it

• If you take this medicine for headaches for more than three days it can make them worse

• Section 2 : Before taking - Do not take

•    This medicine contains codeine which can cause addiction if you take it continuously for more than three days. This can give you withdrawal symptoms from the medicine when you stop taking it

•    If you take a painkiller for headaches for more than three days it can make them worse

• Section 3: Dosage

•    (In the dosage warning section): Do not take for more than 3 days. If you need to use this medicine for more than three days you must speak to your doctor or pharmacist

•    This medicine contains codeine and can cause addiction if you take it continuously for more than three days. When you stop taking it you may get withdrawal symptoms. You should talk to your doctor or pharmacist if you think you are suffering from withdrawal symptoms.

• Section 4: Side effects

• Some people may have side-effects when taking this medicine. If you have any unwanted side-effects you should seek advice from your doctor, pharmacist or other healthcare professional. Also you can help to make sure that medicines remain as safe as possible by reporting any unwanted side-effects via the internet at www.yellowcard.gov.uk; alternatively you can call Freephone 0808 100 3352 (available between 10am-2pm Monday - Friday) or fill in a paper form available from your local pharmacy.

• How do I know if I am addicted?

If you take the medicine according to the instructions on the pack it is unlikely that you will become addicted to the medicine. However, if the following apply to you it is important that you talk to your doctor:

o You need to take the medicine for longer periods of time

o You need to take more than the recommended dose

o When you stop taking the medicine you feel very unwell but you feel better if you start taking the medicine again

4.5 Interactions with other medicinal products and other forms of interaction

May enhance the effects of anticoagulants and inhibit the effects of uricosurics.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

4.6 Pregnancy and lactation

Codeine should not be used during breastfeeding (see section 4.3).

At normal therapeutic doses codeine and its active metabolite may be present in breast milk at very low doses and is unlikely to adversely affect the breast fed infant.

However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolite, morphine, may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant, which may be fatal.

If symptoms of opioid toxicity develop in either the mother or the infant, then all codeine containing medicines should be stopped and alternative non-opioid analgesics prescribed. In severe cases consideration should be given to prescribing naloxone to reverse these effects.

There is clinical and epidemiological evidence for the safety of aspirin in human pregnancy, but it may prolong labour and contribute to maternal and neonatal bleeding and is best avoided at term in the last trimester of pregnancy and during breastfeeding.

4.7 Effects on ability to drive and use machines

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When taking this medicine, patients should be told:

•    The medicine is likely to affect your ability to drive

•    Do not drive until you know how the medicine affects you

•    It is an offence to drive while under the influence of this medicine

•    However, you would not be committing an offence (called ‘statutory defence’) if:

-    The medicine has been taken to treat a medical or dental problem and

-    You have taken it according to the information provided with the medicine and

-    It was not affecting your ability to drive safely

4.8 Undesirable effects

May precipitate bronchospasm and include attacks of asthma or hypersensitivity in susceptible subjects, and may include gastrointestinal hemorrhage, occasionally major.

Regular prolonged use of codeine is known to lead to addiction and symptoms of restlessness and irritability may result when treatment is then stopped.

Prolonged use of a painkiller for headaches can make them worse.

4.9 Overdose Codeine

The effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotrophic drugs.

Symptoms

Central nervous system depression, including respiratory depression, may develop, but is unlikely to be severe unless other sedative agents have been coingested, including alcohol, or the overdose is very large. The pupils may be pin-point in size; nausea and vomiting are common. Hypotension and tachycardia are possible, but unlikely.

Management

This should include general symptomatic and supportive measures, including a clear airway and monitoring of vital signs until stable. Consider activated charcoal if an adult presents within 1 hour of ingestion of more than 350mg or a child more than 5mg/kg.

Give naloxone if coma or respiratory depression is present. Naloxone is a competitive antagonist and has a short half-life, so large and repeated doses may be required in a seriously poisoned patient. Observe for at least 4 hours after ingestion, or 8 hours if a sustained release preparation has been taken.

Salicylates/Aspirin

Salicylate poisoning is usually associated with plasma concentrations >350mg/L (2.5mmol/L). Most adult deaths occur in patients whose concentrations exceed 700mg/b (5.1mmol/L). Single doses less than 100mg/kg are unlikely to cause serious poisoning.

Symptoms

Common features include vomiting, dehydration, tinnitus, vertigo, deafness, sweating, warm extremities with bounding pulses, increased respiratory rate and hyperventilation. Some degree of acid-base disturbance is present in most cases.

A mixed respiratory alkalosis and metabolic acidosis with normal or high arterial pH (normal or reduced hydrogen ion concentration) is usual in adults and children over the age of 4 years. In children aged 4 years or less, a dominant metabolic acidosis with low arterial pH (raised hydrogen ion concentration) is common. Acidosis may increase salicylate transfer across the blood brain barrier.

Uncommon features include haematemesis, hyperpyrexia, hypoglycaemia, hypokalaemia, thrombocytopenia, increased INRIPTR, intravascular coagulation, renal failure and non-cardiac pulmonary oedema.

Central nervous system features, including confusion, disorientation, coma and convulsions, are less common in adults than in children.

Management

Give activated charcoal if an adult presents within 1 hour of ingestion of more than 250mg/kg. The plasma salicylate concentration should be measured, although the severity of poisoning cannot be determined from this alone, and the clinical and biochemical features must be taken into account. Elimination is increased by urinary alkalinisation, which is achieved by the administration of 1.26% sodium bicarbonate. The urine pH should be monitored. Correct metabolic acidosis with intravenous

8.4% sodium bicarbonate (first check serum potassium). Forced diuresis should not be used since it does not enhance salicylate excretion and may cause pulmonary oedema.

Haemodialysis is the treatment of choice for severe poisoning and should be considered in patients with plasma salicylate concentrations >700mg/b (5.1mmoIIL), or lower concentrations associated with severe clinical or metabolic features. Patients under 10 years or over 70 have increased risk of salicylate toxicity and may require dialysis at an earlier stage.

5.1 Pharmacodynamic properties

Aspirin

Aspirin inhibits the cyclo-oxygenase enzyme involved in conversion of phospholipids to prostaglandins and its effect on the body are believed to result primarily from prevention of prostaglandin production. These effects include peripheral analgesia, fever reduction, reduction in inflammation and inhibition of platelet aggregation.

Codeine

Codeine is a centrally acting weak analgesic. Codeine exerts its effects through p opioid receptors although codeine has low affinity for these receptors, and its analgesic effect is due to its conversion to morphine. Its actions include analgesia, inhibition of the cough reflex and reduction in gastrointestinal motility. . Codeine, particularly in combination with other analgesics such as paracetamol, has been shown to be effective in acute nociceptive pain.

5.2 Pharmacokinetic properties

Aspirin

Aspirin is rapidly absorbed from the stomach and upper gastrointestinal tract with peak levels after around 20-30 minutes following dissolution. It is subject to first-pass metabolism with an overall bioavailability of around 70%. Metabolism is by conversion to salicylic acid and then further to other metabolites. These are excreted both free and conjugated mainly by the kidneys. The plasma half-life of aspirin is around 15-20 minutes and of salicylic acid is 2-3 hours.

Codeine

Codeine is well absorbed from the gastrointestinal tract with peak concentrations occurring after around 1 hour. Absorption is rapid and virtually complete with a bioavailability of around 60%. It is metabolised in the liver and excreted mainly in the urine as free and conjugated metabolites. The halflife of codeine in plasma is 2.5-4 hours.

5.3 Preclinical safety data

No preclinical findings of relevance to the prescriber have been reported.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Calcium carbonate Maize starch Citric acid Talc

Sodium lauryl sulphate Saccharin

6.2    Incompatibilities

None known

6.3    Shelf life

Three years

6.4    Special precautions for storage

Store below 30°C in a dry place

6.5    Nature and contents of container

Cardboard carton containing tablets in strips of 30 micron aluminium soft temper foil with the addition of a 12 micron polyester laminate on the unprinted side.

Pack sizes: 8, 12, 16, 24, 32 (Those packs in bold are currently marketed)

6.6    Special precautions for disposal

Tablets to be dissolved in water prior to administration

7    MARKETING AUTHORISATION HOLDER

Reckitt Benckiser Healthcare (UK) Limited

Dansom Lane

Hull

HU8 7DS

8    MARKETING AUTHORISATION NUMBER

PL 00063/0012

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24/04/1995    /    16/09/2005

DATE OF REVISION OF THE TEXT

12/09/2014