This information is intended for use by health professionals

1. Name of the medicinal product

Paracetamol and Codeine 500 mg/ 12.8 mg Tablets

2. Qualitative and quantitative composition

Active ingredient

mg/tablet

Paracetamol

Codeine phosphate hemihydrate

500.0

12.8

Excipient with known effect: sodium metabisulphite (E223)

For full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet

White, pillow shaped tablet, with the letter 'M' debossed on one side.

4. Clinical particulars
4.1 Therapeutic indications

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, ibuprofen or aspirin) alone.

This medicine is recommended for the relief of migraine, headache, dental pain, period pain, backache, arthritic & rheumatic pain, strains & sprains and sciatica.

4.2 Posology and method of administration

Adults (including the elderly)

Two tablets up to 4 times a day. This dose should not be repeated more frequently than every 4 hours, and not more than 4 doses (8 tablets) should be taken in any 24 hour period.

Paediatric population:

Children aged 16 years to 18 years

One to Two tablets up to 4 times a day. This dose should not be repeated more frequently than every 6 hours, and not more than 4 doses (8 tablets) should be taken in any 24 hour period.

Children aged 12 years to 15 years

One tablet up to 4 times a day. This dose should not be repeated more frequently than every 6 hours and not more than 4 doses (4 tablets) should be taken in any in 24 hours period.

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).

For oral administration only.

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

Hypersensitivity to paracetamol, codeine, opioid analgesics or any of the other constituents.

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 breastfeeding (see section 4.6).

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

Do not give to children under 12 years of age (see section 4.4)

4.4 Special warnings and precautions for use

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

Do not exceed the stated dose.

Patients should be advised to consult their doctor if their headaches become persistent. Patients should be advised not to take other paracetamol or codeine-containing products concurrently.

Patients with obstructive bowel disorders or acute abdominal conditions should consult a doctor before using this product.

Patients with a history of cholecystectomy should consult a doctor before using this product as it may cause acute pancreatitis in some patients.

The label will state:

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

Do not take more medicine than the label tells you to.

If you do not get better, talk to your doctor.

Keep all medicines out of the sight and reach of children.

Do not take anything else containing paracetamol while taking this medicine.

Front of pack

• Can cause addiction

• For three days use only

Back of pack

• List of indications as agreed in 4.1 of the SPC

• If you need to take this medicine continuously for more than 3 days you should see your doctor or pharmacist

• This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days. If you take this medicine for headaches for more than 3 days it can make them worse

The leaflet (or combined label/leaflet) will state:

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.

'Headlines' section (to be prominently displayed)

• This medicine can only be used for.....(indications)

• You should only take this product for a maximum of 3 days at a time. If you need to take it for longer than 3 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 3 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 3 days it can make them worse

'What this medicine is for' section

• Succinct description of the indications from 4.1 of the SPC

'Before you take this medicine' section

• This medicine contains codeine which can cause addiction if you take it continuously for more than 3 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 3 days it can make them worse

'How to take this medicine' section

• Do not take for more than 3 days. If you need to use this medicine for more than 3 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 3 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

'Possible side effects' section

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.go.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App store. By reporting side effects you can help provide more information on the safety of this medicine.

'How do I know if I am addicted?' section

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 you doctor:

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

• You need to take more than the recommended amount

• 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 summarised 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% to 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 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.

4.5 Interaction with other medicinal products and other forms of interaction

Paracetamol

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

The anticoagulation 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.

Codeine

Codeine may antagonise the effects of metoclopramide and domperidone on gastrointestinal motility.

The effect of CNS depressants (including alcohol anaesthetics, hypnotics, sedatives, tricyclic antidepressants and phenothiazines.) may be potentiated by codeine; these interactions are unlikely to be significant at the dosage involved.

Opioid analgesics should be given with care to patients receiving monoamine oxidase inhibitors.

4.6 Fertility, pregnancy and lactation

Pregnancy

Use during pregnancy should be avoided, unless advised by a physician. This includes maternal use during labour because of the potential for respiratory depression in the neonate.

The safety of paracetamol-codeine during pregnancy has not been established relative to the possible adverse effects of fetal development.

Codeine

There is inadequate evidence of the safety of codeine in human pregnancy. A possible association with respiratory and cardiac malformation has been reported following first trimester exposure to codeine. Regular use during pregnancy may cause physical dependence in the fetus leading to withdrawal symptoms in the neonate.

Administration of codeine during labour may depress respiration in the neonate.

Opioid analgesics may cause gastric stasis during labour, increasing the risk of inhalation pneumonia in the mother.

Paracetamol.

A large amount of data on pregnant women indicate neither malformative nor feto/neonatal toxicity.

Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

Breast-feeding

Codeine

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 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.

Paracetamol

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

Fertility

There is no information relating to the effects of codeine/paracetamol on fertility.

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 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 a '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

Adverse events from historical clinical trial data are both infrequent and from small patient exposure. Accordingly, events reported from extensive post-marketing experience at therapeutic/labelled dose and considered attributable are tabulated below by system. The following convention has been utilised for the classification of undesirable effects:

Very common (≥1/10), common (≥1/100 to, <1/10), uncommon (≥1/1,000, to <1/100), rare (≥1/10,000 to, <1/1000), very rare (<1/10,000), not known (cannot be estimated from available data).

Paracetamol

Body System

Undesirable effect

Frequency

Blood and lymphatic system disorders

Thrombocytopenia

Agranulocytosis

Not known

Immune system disorders

Anaphylaxis

Cutaneous hypersensitivity reactions including skin rashes and angioedema.

Not known

Skin and subcutaneous tissue disorders

Serious skin reactions

Very rare

Respiratory, thoracic and mediastinal disorders

Bronchospasm*

Not known

Hepatobiliary disorders

Hepatic dysfunction

Not known

* There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.

Codeine

Adverse reactions identified during post-marketing use are listed below by MedDRA system organ class.

Body System

Undesirable effect

Frequency

Psychiatric disorders

Drug dependency can occur after prolonged use of codeine at higher doses

Not known

Gastrointestinal disorder

Constipation, nausea, vomiting, dyspepsia, dry mouth, acute pancreatitis in patients with a history of cholecystectomy

Not known

Nervous system disorder

Dizziness, worsening of headache with prolonged use, drowsiness

Not known

Skin and subcutaneous tissue disorder

Pruritus, sweating

Not known

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 professional 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 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors:-

Risk Factors:

If the patient

a) Is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John's Wort or other drugs 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.

Management

Immediate treatment is essential in the management of paracetamol overdosage. 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) but results should not delay initiation of treatment beyond 8 hours after ingestion, as 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.

Codeine

The effects of codeine 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 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.

Management

Management 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 4 hours after ingestion.

5. Pharmacological properties
5.1 Pharmacodynamic properties

ATC code: N02B E51.

Paracetamol is both a centrally and peripherally acting analgesic with antipyretic activity.

Codeine is a centrally acting weak analgesic. Codeine exerts its effect through mu 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 absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 30 minutes to 2 hours after ingestion. Paracetamol is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates, with about 10% as glutathione conjugates. Less than 5% is excreted as unchanged paracetamol. The plasma half-life is around 2 hours. Plasma protein binding is negligible at usual therapeutic concentrations, although this is dose dependent.

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. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid. The plasma half-life is variable between 2 and 3.5 hours.

5.3 Preclinical safety data

Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.

6. Pharmaceutical particulars
6.1 List of excipients

Pregelatinised maize starch

Maize starch

Microcrystalline cellulose

Purified water

Dried maize starch

Magnesium stearate

Sodium metabisulphite

6.2 Incompatibilities

None stated.

6.3 Shelf life

36 months

6.4 Special precautions for storage

Store in the original package.

6.5 Nature and contents of container

A child-resistant push through pack of white opaque 250 micron PVC/40gsm PVdC blisters heat sealed to 35gsm Glassine paper/9 micron soft temper aluminium foil.

Pack sizes: 6/8/10/12/16/18/20/24/25/30/32

6.6 Special precautions for disposal and other handling

Not applicable.

7. Marketing authorisation holder

The Boots Company PLC

1 Thane Road West

Nottingham NG2 3AA

England

8. Marketing authorisation number(s)

PL 00014/0865

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 01 August 2019

10. Date of revision of the text