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1.    NAME OF THE MEDICINAL PRODUCT

Co-codamol 15mg/500mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

mg per tablet

Paracetamol    500.0mg

(as Paracetamol DC 96% and Povidone 4%)

Codeine Phosphate Hemihydrate    15.0mg

For a full list of excipients, see Section 6.1

3    PHARMACEUTICAL FORM

Tablet.

Oblong, white uncoated tablets marked ‘K1 ’ both sides of a score line on one side, the other side is plain and unmarked. The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

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:

Two tablets to be taken every four hours as required, up to a maximum of eight tablets in any 24-hour period.

Paediatric population: Children aged 16 and over:

Two tablets to be taken every six hours as required, up to a maximum of eight tablets in any 24-hour period.

Children aged 12 to 15 years:

One tablet to be taken every six hours as required, up to a maximum of four tablets in any 24-hour 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).

Elderly:

The adult dose is appropriate (please refer to Section 4.4 for additional information on elderly patients).

The duration of treatment should be limited to three 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

Co-Codamol 15mg/500mg Tablets should not be used in patients hypersensitive to codeine phosphate, paracetamol or any of the other ingredients. This product is contraindicated in patients with raised intracranial pressure or head injury, respiratory depression, acute asthma and acute alcoholism. Co-Codamol 15mg/500mg Tablets are also contraindicated in patients receiving monoamine oxidase inhibitors or who have received these agents within the previous two weeks.

This product is contraindicated in women during breastfeeding (see section 4.6) and also in patients for whom it is known they are CYP2D6 ultra-rapid metabolisers.

Co-Codamol 15mg/500mg Tablets are contraindicated 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).

Co-Codamol 15mg/500mg Tablets are not recommended for children under 12 years of age.

4.4 Special warnings and precautions for use 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%

Co-Codamol 15mg/500mg Tablets should be used with caution in the elderly and debilitated as these patients may be more sensitive to the effects of opioids, those with prostatic hypertrophy, inflammatory or obstructive bowel disorders or Addison’s disease. 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. Dependence of the morphine type may be produced especially with prolonged use of high doses of codeine.

Prolonged regular use, except under medical supervision, may lead to physical and psychological dependence (addiction) and result in withdrawal symptoms such as restlessness and irritability, once the drug is stopped.

The risk-benefit of continued use should be assessed regularly by the prescriber.

Immediate medical advice should be sought in the event of an overdose, even if the patient feels well, because of the risk of delayed serious liver damage. Patients should be advised not to take other paracetamol- or codeine-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.

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.

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

The depressant effects of codeine may be enhanced by other central nervous system depressants: anxiolytics, hypnotics, antidepressants, antipsychotics and alcohol. If combined therapy is necessary, the dose of one or both agents should be reduced. Alcohol should be avoided.

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 use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

4.6    Fertility, pregnancy and lactation

This product should not be used during pregnancy.

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.

4.7    Effects on ability to drive and use machines

Co-Codamol 15mg/500mg Tablets may impair mental and/or physical abilities, therefore it may affect the ability to drive and 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:

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

The following undesirable effects have been reported following the use of paracetamol: blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol. Hypersensitivity, including skin rash, may also occur. Very rare cases of serious skin reactions have been reported.

The following undesirable effects have been reported following the use of codeine: nausea, vomiting, dizziness and drowsiness. These effects are more likely to be experienced by the ambulatory patient and thus may be alleviated if the patient lies down. Other side effects of codeine, which may occur, include bradycardia, miosis, constipation, abdominal pain (rarely codeine-induced pancreatitis has been reported in patients with a history of cholecystectomy), allergic reactions, light-headedness, confusion, euphoria, dysphoria, urinary retention, and pruritus.

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.

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

4.9 Overdose

Paracetamol Overdose

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, 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 of Paracetamol Overdose

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 of Paracetamol Overdose

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.

Treatment with activated charcoal should be considered if the overdose has been taken within one 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 with serious hepatic dysfunction beyond 24 hours from ingestion should be discussed with the National Poisons Information Centre (NPIC) or a liver unit.

Codeine Overdose

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

Symptoms of Codeine Overdose

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 of Codeine Overdose

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.

5.1    Pharmacodynamic properties

Pharmacotherapeutic Group: Paracetamol, combinations, excluding psycholeptics ATC Code: N02B E51

Paracetamol has analgesic and antipyretic effects that do not differ significantly from those of aspirin. Its anti-inflammatory action is weak and it has practically no anti-platelet effect. The mechanism of action is unclear, although it is believed to exert its action by inhibition of prostaglandin synthesis.

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. 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 two hours after oral administration. 90-100% of administered drug can be    recovered in the    urine within the first    day.    Practically    none is

excreted unchanged, most is    conjugated in the    liver with glucuronic    acid or    sulphuric    acid.

Codeine and its salts are absorbed rapidly from the gastrointestinal tract with peak plasma levels occurring about one hour after oral administration. Codeine is metabolised in the liver and excreted in the urine mainly as a conjugate of glucuronic acid. Approximately 10% of administered codeine is demethylated to form morphine.

Concurrent administration of both drugs does not interfere with the normal metabolic processes of each agent.

5.3    Preclinical safety data

There are no findings of relevance to the prescriber other than those already mentioned elsewhere in the SPC.

6    PHARMACEUTICAL    PARTICULARS

6.1    List of excipients

Microcrystalline Cellulose Magnesium Stearate

10 DATE OF REVISION OF THE TEXT

14/01/2015