This information is intended for use by health professionals

1. Name of the medicinal product

Co-codamol 8 mg/500 mg effervescent tablets

2. Qualitative and quantitative composition

Each effervescent tablet contains 8 mg codeine phosphate hemihydrate and 500 mg paracetamol

Excipients with known effects

Each effervescent tablet contains 5 mg of aspartame

Each effervescent tablet contains 438 mg of sodium.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Effervescent tablets.

White circular, flat bevelled edge tablet, plain on both sides.

4. Clinical particulars
4.1 Therapeutic indications

Co-codamol (which contains codeine) are indicated in patients older than 12 years of age for short term the treatment of acute moderate pain (such as muscular and rheumatic pains, headache, migraine, neuralgia, toothache, period pains, aches and pains) which is not considered to be relieved by other analgesics such as paracetamol, ibuprofen or aspirin alone.

4.2 Posology and method of administration

Posology

Co-codamol should be used at the lowest effective dose for the shortest period of time. This dose may be taken up to 4 times a day, at intervals of not less than 4-6 hours, depending on the age of the patient (see below). Maximum daily dose of codeine should not exceed 240mg.

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.

Adults

One to two tablets dissolved in water every 4 to 6 hours as required, to a maximum of 8 tablets daily.

Elderly

There is no current evidence for the alteration of the adult dose except where there is impaired hepatic function when dosage reduction may be necessary.

Paediatric population

Children aged 12 years to 15 years

The recommended Co-codamol dose for children 12 years old to 15 years old is 1 tablet dissolved in water every 6 hours when necessary up to a maximum of 4 tablets in 24 hours.

Children aged 16 years to 18 years

The recommended Co-codamol dose for children 16 years old to 18 years old is 1 to 2 tablets dissolved in water every 6 hours when necessary up to a maximum of 8 tablets daily.

Children aged below 12 years

Co-codamol (which contains 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).

Method of administration

For oral use.

Co-codamol should be dissolved in at least half a glass of water. The resulting solution should be stirred well before oral administration.

4.3 Contraindications

Conditions where morphine and opioids are contra-indicated e.g. acute alcoholism and where risk of paralytic ileus, acute respiratory depression, raised intracranial pressure or head injury (affects pupillary responses vital for neurological assessment).

Hypersensitivity to codeine or paracetamol or to any of the excipients listed in section 6.1.

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)

In women during breast-feeding (see section 4.6)

In patients for whom it is known they are CYP2D6 ultra-rapid metabolisers

4.4 Special warnings and precautions for use

Other paracetamol containing medication should be avoided when taking Co-codamol effervescent tablets.

These tablets contain sodium (438 mg) and should be avoided by patients on a low sodium diet. The tablets contain aspartame and so should not be taken by patients with phenylketonuria.

Care should be taken when prescribing these tablets to patients with liver or renal impairment.

The hazards of paracetamol overdose are greater in those with non-cirrhotic alcoholic liver disease.

Because safety and effectiveness in the administration of Paracetamol with codeine in children under 12 years of age have not been established, such use is not recommended.

These tablets should be used with caution in patients with caution in patients with head injuries, conditions in which intracranial pressure is raised, in patients sensitive to the effects of opioids, e.g. the elderly and debilitated patients, with CNS depression, hypothyroidism.

Addison's disease, prostatic hypertrophy or urethral stricture, myasthenia gravis, inflammatory or obstructive bowel disorders, pre-existing respiratory depression or those with the potential to develop respiratory depression. Care is advised in the administration of Paracetamol to patients with severe renal or severe hepatic impairment. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Severe liver damage may occur if the maximal daily dose is exceeded, if Co- codamol is taken together with another Paracetamol containing product, or if Co-codamol is taken while consuming large amounts of alcohol.

Administration of pethidine and possibly other opioid analgesics to patients taking a monoamine oxidase inhibitor (MAOI) has been associated with very severe and sometimes fatal reactions. If the use of codeine is considered essential then great care should be taken in patients taking MAOI's or within 14 days of stopping MAOI's (see section 4.5).

Although Paracetamol might logically be presumed to be the best alternative analgesic in patients with aspirin sensitivity, cross reactions have been reported. Patients positively identified with aspirin induced asthma, or who have ever experienced an asthmatic reaction to aspirin or non-steroidal anti- inflammatory drugs (NSAID's) or are at high risk or aspirin induced asthma should avoid all products that contain aspirin or NSAID's indefinitely. In these patients Paracetamol should be recommended in low moderate dose (<1000mg in a single dose) unless contraindicated.

At high dose codeine has most of the disadvantages of morphine, including respiratory depression. Codeine can produce drug dependence of the morphine type, and therefore has the potential for being abused. Codeine may impair the mental/or physical abilities required for the performance of potentially hazardous tasks.

Patients should be advised that immediate medical advice should be sought in the event of an overdose, because of the risk of delayed, serious liver damage. They should be advised not to exceed the recommended dose, not to take other Paracetamol containing products concurrently, to consult their doctor if symptoms persist and to keep the product out of reach.

The label will state:

Front of pack

• Can cause addiction

• For three days use only

Back of pack

• This medicine can only be used 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.

• For the treatment of pain, including muscular and rheumatic pains, headache, migraine, neuralgia, toothache, period pains, aches and pains.

• 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.

• Contains paracetamol.

• Do not take more medicine than the label tells you to. If you do not get better, talk to your doctor.

• Do not take anything else containing paracetamol while taking this medicine. Talk to a doctor at once if you take too much of this medicine, even if you feel well.

The leaflet will state:

Headlines section (to be prominently displayed)

• This medicine can only be used for the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone.

• You should only take this medicine 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 1: What Co-codamol is and what it is used for

• This medicine can only be used for the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone. It is used to relieve muscular and rheumatic pains, headache, migraine, neuralgia (severe burning or stabbing pain following the line of a nerve), toothache, period pains, aches and pains.

Section 2: What you need to know before you take Co-codamol

• 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: How to take Co-codamol

• Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

• Do not exceed the recommended doses.

• Talk to a doctor at once if you take too much of this medicine even if you feel well.

• This is because too much paracetamol can cause delayed, serious liver damage.

• 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.

• This medicine should not be taken for more than 3 days. If the pain does not improve after 3 days, talk to your doctor for advice.

Section 4: Side effects

• Some people may have side-effects when taking this medicine.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

By reporting side effects you can help provide more information on the safety of this medicine.

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:

• You need to take the medicine for longer periods of time.

• You need to take more than the recommended dose.

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

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 post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life-threatening adverse events including death (see 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 leaflet will state in the “Pregnancy and breast-feeding” subsection of section 2 “Before taking your medicine”:

Although there is no evidence that these tablets cause any ill effects during pregnancy, your doctor should advise you about taking them if you are pregnant.

Do not take codeine while you are breastfeeding. Codeine and morphine passes into breast milk.

4.5 Interaction with other medicinal products and other forms of interaction

Avoid taking co-codamol effervescent tablets with CNS depressants or other paracetamol containing products.

Opioid analgesics such as codeine antagonise the effects of domperidone or metoclopramide on gastrointestinal activity.

Paracetamol should be given with care to patients taking other medicinal products which affect the liver.

The speed of absorbtion of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine.

The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding: Occasional doses have no significant effect.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is inadequate evidence of safety of the active substance in human pregnancy, but it has been in wide use for many years without apparent ill-consequence, although there is evidence that exposure to codeine during pregnancy may give a higher incidence of respiratory malformations. If active substance therapy is needed in pregnancy, this medicinal product can be used if there is no safer alternative. At normal doses, low levels of paracetamol and codeine are present in breast milk.

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use.

Opioid analgesics may depress neonatal respiration and cause withdrawal effects in neonates of dependent mothers. There is a risk of gastric stasis and of inhalation pneumonia in mothers during labour.

Breast-feeding

Paracetamol is excreted in the breast milk but not in a clinically significant amount. Available published data do not contraindicate breast-feeding. However, codeine should not be used during breastfeeding (see section 4.3).

At normal therapeutic doses codeine and its active metabolites 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 metabolites, 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.

Therefore, this product should not be used during breastfeeding (see section 4.3).

4.7 Effects on ability to drive and use machines

Patients should be warned not to drive or operate machinery if they become dizzy or sedated while taking co-codamol effervescent tablets.

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 medicinal products included in regulations under 5a of the Road Traffic Act 1988. When prescribing 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:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

4.8 Undesirable effects

Co-codamol effervescent tablets are generally well tolerated but hypersensitivity reactions including skin rashes may occur.

Immune system disorders

Rare cases of anaphylaxis, angioedema, urticaria, pruritus and fixed drug eruption have been reported with medications containing paracetamol and/or codeine.

Blood and the lymphatic system disorders

There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis but these were not necessarily causally related to Co-codamol.

Codeine may sometimes cause typical opioid effects such as:

Gastrointestinal disorders

Constipation, nausea, abdominal pain.

Nervous system disorders

Light- headedness, headache, dizziness, confusion, drowsiness

Renal and urinary disorder

Urinary retention

The frequency and severity of these effects are determined by dosage, duration of treatment and individual sensitivity. There have been rare reports of acute pancreatitis in patients taking codeine or codeine/paracetamol combinations.

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

• Long-term usage of high doses of codeine + paracetamol can be rarely associated with ototoxicity leading to sensorineural hearing loss.

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

Skin and subcutaneous tissue disorders

Very rare cases of serious skin reactions such as Stevens - Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Paracetamol

Liver damage is possible in adults who have taken 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk factors

If the patient

a. Is on long term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St John's Wort or other medicinal products that induce liver enzymes.

or

b. Regularly consumes ethanol in excess of recommended amounts.

or

c. Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Treatment

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.

Codeine

Nausea and vomiting are prominent symptoms of codeine toxicity, with circulatory and respiratory depression in severe overdose.

The effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic medicinal products.

Symptoms

Central nervous system depression, including respiratory depression, may develop but is unlikely to be severe unless other sedative agents have been co-ingested, 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.

Treatment

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 one hour of ingestion of more than 350 mg or a child more than 5 mg/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 four hours after ingestion, or eight hours if a sustained release preparation has been taken.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anilides, Paracetamol combinations

ATC Code: NO2B E51

Paracetamol/Codeine has antipyretic and analgesic actions with little anti-inflammatory effect.

Codeine is a centrally acting weak analgesic. Codeine exerts its effect through μ opioid receptors, although codeine has low affinity for these receptors, and its analgesic effect is due to its conversion to morphine. Codeine, particularly in combination with other analgesics such as paracetamol, has been shown to be effective in acute nociceptive pain.

5.2 Pharmacokinetic properties

Paracetamol is rapidly and well absorbed from the intestinal tract after it has left the stomach. Plasma protein binding is low and paracetamol is metabolised in the liver and mainly excreted in the urine as glucuronide and sulphate conjugates. The elimination half-life is 1-3 hours.

Codeine is absorbed from the gastro-intestinal tract and peak plasma-codeine concentrations are found in about one hour. It is metabolised by O- and N-demethylation in the liver to morphine, norcodeine, and other metabolites including normorphine and hydrocodone. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid. The elimination half-life has been reported to be between 3 and 4 hours.

5.3 Preclinical safety data

None stated

6. Pharmaceutical particulars
6.1 List of excipients

Sodium hydrogen carbonate,

Citric acid,

Sodium carbonate anhydrous,

Povidone,

Simeticone,

Sodium saccharin,

Aspartame,

Polysorbate 80.

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 25°C.

Store in a dry place and protect from light.

6.5 Nature and contents of container

4 layer paper/PE/aluminium/PE blisters.

Pack sizes: 7, 10, 14, 20, 28, 30 and 32 tablets.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

7. Marketing authorisation holder

Cipla (EU) Limited,

Dixcart House, Addlestone Road,

Bourne Business Park, Addlestone,

Surrey, KT15 2LE, United Kingdom.

8. Marketing authorisation number(s)

PL 36390/0005

9. Date of first authorisation/renewal of the authorisation

06/10/2011

10. Date of revision of the text

30/03/2018.