This information is intended for use by health professionals

1. Name of the medicinal product

Co-codamol 15 mg/500 mg Tablets

2. Qualitative and quantitative composition

Each tablet contains: Paracetamol 500 mg and Codeine Phosphate Hemihydrate 15 mg.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablets.

Off-white, capsule-shaped tablets approximately 17.50mm in length.

Engraved on one side with “CO COD 15” and plain on the reverse.

4. Clinical particulars
4.1 Therapeutic indications

For the relief of moderate pain.

Codeine is indicated in patients older than 12 years of age for the treatment of acute moderate pain which is not considered to be relieved by other analgesics such as paracetamol or ibuprofen (alone).

4.2 Posology and method of administration

For oral administration.

Adults:

One or two tablets not more frequently than every 4- 6 hours, up to a maximum of 8 tablets in any 24 hour period.

Elderly:

Same as for adults, however a reduced dose may be required (see section 4.4).

Paediatric population:

Children aged 16-18 years: One or two tablets every 6 hours when necessary up to a maximum of 8 tablets in 24 hours.

Children aged 12 – 15 years: One tablet every 6 hours when necessary up to a maximum of 4 tablets in 24 hours.

Children aged less than 12 years: 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).

4.3 Contraindications

Known hypersensitivity to paracetamol, codeine or to any of the other ingredients.

Conditions where morphine and opioids are contraindicated eg:

- hepatocellular insufficiency

- acute asthma

- respiratory depression

- acute alcoholism

- head injuries

- raised intra-cranial pressure

- following biliary tract surgery

- monoamine oxidase inhibitor therapy, concurrent or within 14 days.

In women during breastfeeding (see section 4.6).

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

4.4 Special warnings and precautions for use

Care should be observed in administering the product to any patient whose condition may be exacerbated by opioids, including the elderly, who may be sensitive to their central and gastro-intestinal effects; those on concurrent CNS depressant drugs, those with prostatic hypertrophy and those with inflammatory or obstructive bowel disorders, Addison's disease or myasthenia gravis.

Care should also be observed if prolonged therapy is contemplated. The risk-benefit of continued use should be assessed regularly by the prescriber.

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 ultra-rapid 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.

Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazard of overdose with paracetamol is greater in those with alcoholic liver disease.

Patients should be advised not to take other paracetamol containing products concurrently.

The leaflet will state in a prominent position in the 'Before Taking' section:

• Do not take for longer than directed by your prescriber

• Taking codeine regularly for a long time can lead to addiction, which might cause you to feel restless and irritable when you stop the tablets

• Taking a painkiller for headaches too often or for too long can make them worse.

Under 'Pregnancy and Breastfeeding' sub-section:

Do not take codeine while you are breast feeding. Codeine and morphine pass into breast milk.

In Section 3 'How to take Co-codamol tablets':

Talk to your 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.

The label will state (to be displayed prominently on outer pack – not boxed):

• Do not take for longer than directed by your prescriber as taking codeine regularly for a long time can lead to addiction

• 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.

4.5 Interaction with other medicinal products and other forms of interaction

The effects of CNS depressants (including other opioid analgesics, tranquilisers, sedative hypnotics and alcohol) may be potentiated by codeine.

When such therapy is contemplated, the dose of one or both agents should be reduced.

Paracetamol may increase the elimination half-life of chloramphenicol. Oral contraceptives may increase its rate of clearance.

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

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

The effects of CNS depressants (including alcohol) may be potentiated by codeine.

4.6 Fertility, pregnancy and lactation

Pregnancy:

Careful consideration should be given before prescribing the product to pregnant patients. Opioid analgesics may depress neonatal respiration and cause withdrawal effects in neonates of dependent mothers.

Co-codamol should not be used during pregnancy.

Lactation:

Paracetamol is excreted in breast milk but not in a clinically significant amount.

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.

Fertility:

There are no data on the effects of Co-codamol on human fertility. Fertility was unaffected following paracetamol or codeine treatment in animal studies.

4.7 Effects on ability to drive and use machines

Codeine may cause drowsiness and if affected patients should be advised not to drive or operate machinery.

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 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:

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

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

- It was not affecting your ability to drive safely

4.8 Undesirable effects

The frequency and severity of codeine side effects are determined by dosage, duration of treatment and individual sensitivity.

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.

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

The information below lists reported adverse reactions using the frequency classification: Very rare = <1/10,000. Not known = cannot be estimated from the available data.

Blood and lymphatic system disorders:

Frequency not known: blood dyscrasias including agranulocytosis and thrombocytopenia.

Immune system disorders:

Frequency not known: Hypersensitivity including skin rash, anaphylactic shock, angioedema.

Hepatobiliary disorders:

Not known: cytolytic hepatitis, which may lead to acute hepatic failure

Nervous system disorders:

Frequency not known: dizziness, light-headedness, confusion, drowsiness

Ear and labyrinth disorders:

Frequency not known: ototoxicity leading to sensorineural hearing loss.

Gastrointestinal disorders:

Very rare: occurrences of pancreatitis.

Frequency not known: constipation, nausea, vomiting.

Renal and urinary disorders:

Frequency not known: urinary retention.

Skin and subcutaneous disorders:

Very rare cases of serious skin reactions such as toxic epidermal necrolysis, Stevens- Johnson Syndrome, acute generalised exanthematous pustulosis and fixed drug eruption have been reported.

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Paracetamol

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

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

b) regularly consumes ethanol in excess of recommended amounts

c) is likely to be glutathione depleted 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, coma 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.

Management

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 at 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 serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.

Codeine

The effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic 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 one 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 four hours after ingestion, or eight hours if a sustained release preparation has been taken.

5. Pharmacological properties
5.1 Pharmacodynamic properties

ATC Code: N02B E51. Paracetamol, combinations excl psycholeptics.

Paracetamol is an analgesic with antipyretic activity. It acts peripherally, probably by blocking impulse generation at the bradykinin sensitive chemoreceptors which evoke pain. Although it is a prostaglandin synthetase inhibitor, the synthetase system in the CNS rather than the periphery appears to be more sensitive to it. This may explain paracetamols lack of appreciable anti-inflammatory activity.

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 readily and almost completely absorbed from the gastrointestinal tract with peak plasma levels occurring about 30 minutes to 60

minutes after ingestion. It is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted unchanged.

The elimination half-life of paracetamol varies from about 1 to 4 hours.

Plasma protein binding is negligible at usual therapeutic doses.

Codeine phosphate is absorbed from the gastrointestinal tract and peak plasma concentrations occur after about one hour. Codeine is metabolised by O-and N- demethylation in the liver to morphine, and norcodeine and other metabolites. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid.

Codeine is not extensively bound to plasma proteins. The plasma half-life varies from about 3 to 4 hours.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are not already covered in other sections of the SPC.

6. Pharmaceutical particulars
6.1 List of excipients

Maize starch

Colloidal anhydrous silica

Povidone

Potassium sorbate

Magnesium stearate

6.2 Incompatibilities

Not applicable

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 25 °C. Store in the original package.

6.5 Nature and contents of container

Aluminium/PVC blisters (Child resistant constructed from 250 micron PVC film lidded with 9 micron aluminium foil/36gsm paper).

Pack size of 100 tablets.

6.6 Special precautions for disposal and other handling

Not applicable.

7. Marketing authorisation holder

M & A Pharmachem Ltd

Allenby Laboratories

Wigan Road,

Westhoughton,

Bolton

BL5 2AL

8. Marketing authorisation number(s)

PL 04077/0251

9. Date of first authorisation/renewal of the authorisation

21/03/2019

10. Date of revision of the text

21/03/2019