CO-CODAMOL 8/500 TABLETS BP - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Co-codamol 8mg/500mg Tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains Codeine Phosphate 8mg and Paracetamol 500mg

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet for oral use

White, circular tablets marked CDM with a breakline on one face and CP on the reverse.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Co-codamol 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).

For, headache, migraine, toothache, period pains, rheumatic pains, including muscle pains and backache.

4.2 Posology and method of administration

Posology

Adults:      One or two tablets to be taken every four to six hours, when necessary

up to four times daily. Maximum dose of 8 tablets in 24 hours.

Elderly: As for adults, however a reduced dose may be required.

The dose should not be repeated more frequently than every four hours for adults. Not more than 4 doses should be administered in any 24 hour period.

Paediatric Population:

Children aged 16 – 18 years: Take one to two tablets every six hours when necessary up to a maximum of 8 tablets in 24 hours.

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

The dose should not be repeated more frequently than every six hours. Not more than 4 doses should be administered in any 24 hour period.

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.

Children under 12 years

Not recommended for children under 12 years of age because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see section 4.3 and 4.4).

Method of administration:

Oral administration only.

4.3 Contraindications

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.

a) Paracetamol:

Known hypersensitivity to Paracetamol or any of the constituents.

b) Codeine

Known hypersensitivity to Codeine or other opioid analgesics

Moderate to severe renal failure

Moderate to severe liver disease

Respiratory depression and obstructive airways disease

Bronchial asthma attack or heart failure secondary to chronic lung disease

Raised intracranial pressure, head injuries and acute alcoholism

Diarrhoea associated with pseudomembranous colitis. Diarrhoea caused by poisoning until toxic material has been eliminated from gastrointesti­nal tract.

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 summarized below:

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.

The label will state (To be displayed prominently on outer pack):

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

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/dihydro­codeine (DHC) 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 two long can make them worse.

4.5 Interaction with other medicinal products and other forms of interaction

a) Paracetamol:

Paracetamol may delay the elimination of chloramphenicol.

The speed of absorption 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.

Drugs which induce hepatic microsomal enzymes, such as alcohol and barbiturates, may increase the hepatotoxicity of paracetamol, particularly after overdosage.

b) Codeine:

The depressant effects of Codeine are enhanced by depressants of the central nervous system such as alcohol, anaesthetics, hypnotics, sedatives, tricyclic antidepressants and phenothiazines. The hypotensive actions of diuretics and anti-hypertensive agents may be potentiated when used concurrently with opioid analgesics. Concurrent use of hydroxyzine with Codeine may result in increased analgesia as well as increased CNS depressant and hypotensive effects.

Concurrent use of Codeine with antidiarroheal and anti-peristaltic agents such as loperamide and kaolin may increase the risk of severe constipation. Concomitant use of antimuscarine or medications with antimuscarinic action may result in an increased risk of severe constipation which may lead to paralytic ileus and/or urinary retention. The respiratory depressant effect caused by neuromuscular blocking agents may be addictive to the central respiratory depressant effects of opioid analgesics. CNS depression or excitation may occur if Codeine is given to patients receiving monoamine oxidase inhibitors, or within two weeks of stopping treatment with them. Quinidine can inhibit the analgesic effect of Codeine.

Codeine may delay the absorption of mexiletine and thus reduce the antiarrythmic effect of the latter. Codeine may antagonise the gastrointestinal effects of metoclopramide, cisapride and domperidone. Cimetidine inhibits the metabolism of opioid analgesics resulting in increased plasma concentrations.

Naloxone antagonises the analgesics, CNS and respiratory depressant effects of opioid analgesics.

Naltrexone also blocks the therapeutic affect of opioids.

Interference with laboratory tests: Opioid analgesics interfere with a number of laboratory tests including plasma amylase, lipase, bilirubin, alkaline phosphatase, lactate: dehydrogenate, alanine aminotransferase and aspartate aminotranserase. Opioids may also interfere with gastric emptying studies as they delay gastric emptying and with hepatobiliary imaging using technetium Tc 99m disofenin as opioid treatment may cause constriction of the sphincter of Oddi and increase biliary tract pressure.

4.6 Fertility, Pregnancy and lactation

a) Paracetamol

Paracetamol crosses the placenta. There is no known hazard in normal dosage, but like all non-essential medications, Paracetamol should be avoided, especially during the first trimester, unless considered essential by the Physician.

Paracetamol is excreted in breast milk, but there is no evidence that this is clinically significant.

b) Codeine:

Codeine crosses the placenta. There is no adequate evidence of safety in human pregnancy and a possible association with respiratory and cardiac malformations has been reported. Regular use during pregnancy can cause physical dependence in the foetus leading to withdrawal symptoms in the neonate. Use during pregnancy should be avoided if possible.

Use of opioid analgesia during labour may cause respiratory depression in the neonate, especially the premature neonate. These agents should not be given during the delivery of a premature baby.

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

a) Paracetamol:

None.

b) Codeine:

May cause drowsiness; if affected patients should be advised not to drive or operate machinery.

4.8 Undesirable effects

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.

a) Paracetamol:

Adverse effects of paracetamol are rare but hypersensitivity including skin rash may occur. Very rare cases of serious skin reactions have been reported.

There have been a few reports of blood dyscrasias including thrombocytopenia and agranlocytosis but these were not necessarily causally related to paracetamol.

b) Codeine:

Less frequent effects are nausea, vomiting, sweating, facial flushing, dry mouth, blurred or double vision, dizziness, orthostatic hypotension, malaise, tiredness, headache, anorexia, vertigo, bradycardia, palpitations, respiratory depression, dyspnoea, allergic reactions (itch, skin rash, facial oedema) and difficulties in micturition (dysuria, increased frequency, decrease in amount). Side effects which occur rarely include convulsions, hallucinations, nightmares, uncontrolled muscle movements, muscle rigidity, mental depression and stomach cramps.

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

a) 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, 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 48hours 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 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 emote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24 hours from ingestion should be discussed with the NPIS or a liver unit.

b) 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 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

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 witin 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 shelf 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 PHARMALOGICAL PROPERTIES

5.1 Pharmacodynamic properties

a) Paracetamol

Paracetamol is an effective analgesic and antipyretic agent but has only weak antiinflammatory properties. Its mechanism of action is not fully understood. It has been suggested that it may act predominantly by inhibiting prostaglandin synthesis in the CNS and to a lesser extent through a peripheral action by blocking pain-impulse generation. The peripheral action may also be due to inhabitation of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitive pain receptors to mechanical or chemical stimulation. Paracetamol probably produces an antipyretic action by a central effect on the hypothalamic heat-regulating centre to produce peripheral vasodilatation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus. The drug has no effect on the cardiovascular and respiratory systems and unlike salicylates, it does not cause gastric irritation or bleeding.

b) Codeine

Codeine is a centrally acting weak analgesic. Codeine exerts its effect through li opiod 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. Opioid analgesics bind with sterospecific receptors at many sites within the CNS to alter processes affecting both the perception of pain and the emotional response to it. It has been hypothesised that alterations in release of various neurotransmitters from afferent nerve sensitive to painful stimuli may be partially responsible for the analgesic effect. Codeine also has antitussive properties, probably via a direct suppressant action on the cough to relax at the level of the brainstem.

Codeine also acts locally on intestinal smooth muscle and perhaps centrally to reduce intestinal motility.

5.2 Pharmacokinetic properties

a) Paracetamol

Paracetamol is readily absorbed form the gastrointestinal tract with peak plasma concentrations occurring about 30 minutes to 2 hours after ingestion. It is metabolised in the liver (90–95%) and excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted as unchanged Paracetamol. The elimination half-life varies from about 1 to 4 hours. Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations.

A minor hydroxylated metabolite (N-acetyl-p-benzoquinoneimine) (which is usually produced in very small amounts by mixed function oxidases in the liver which is usually detoxified by conjugation with liver glutathione) may accumulate following Paracetamol overdosage and cause liver damage. The time to peak concentrations of Paracetamol is 0.5–2 hours, the time to peak effect 1–3 hours and the duration of action 3 to 4 hours.

b) Codeine

Codeine is absorbed form the gastrointestinal tract and peak plasma concentrations occur after one hour. Codeine is metabolised by 0 – and N- demethylation in the liver to morphine, 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 has been reported to be between 3 and 4 hours.

5.3 Preclinical safety data

Paracetamol & Codeine

There is no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of SPC.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Pregelatinised Maize Starch

Magnesium Stearate

Povidone K30

*Purified Water

*Removed during the granulation procedure.

6.2 Incompatibilities

Not applicable

6.3 Shelf life

24 months

36 months

Blister packs

Polypropylene/po­lyethylene containers

6.4 Special precautions for storage

Do not store above 25°C

Store in original container

6.5 Nature and contents of container

500 or 1000 tablets in polypropylene/po­lyethylene containers, with polypropylene/po­lyethylene tamper evident closures or 100 tablets in blister strips of aluminium foil and PVC film in cartons.

6.6 Special precautions for disposal

None

7. MARKETING AUTHORISATION HOLDER

Aspar Pharmaceuticals Limited

29–30 Capitol Way

Capitol Way Industrial Park, Colindale

London

NW9 0EQ

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

PL 08977/0039

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

25/06/2002 / 10/06/2011