This information is intended for use by health professionals

1. Name of the medicinal product

Co-codamol 30/500mg Effervescent Tablets.

2. Qualitative and quantitative composition

Each tablet contains 30mg codeine phosphate hemihydrate and 500mg paracetamol.

Excipient(s) with known effect

Each tablets contains 438mg of Sodium and 5mg of Aspartame

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Effervescent tablet.

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

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 or ibuprofen (alone).

4.2 Posology and method of administration

For oral administration only. The tablets should be dissolved in at least half a tumbler of water before taking.

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 not more frequently than every 4 hours to a maximum of 8 tablets in 24 hours.

Paediatric Population

Children 16-18 years:

One to two tablets every 6 hours when necessary to a maximum of 8 tablets in 24 hours

Children 12-15 years of age.

One tablet dissolved in water every 6 hours when necessary 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).

Elderly

A reduced dose may be required.

Dosage is adjusted according to a patient's response and the severity of the pain, however tolerance to codeine may develop with prolonged use and care should be taken as adverse effects are dose related.

4.3 Contraindications

• Sensitivity to codeine or paracetamol which is rare or any of the constituents of the tablets.

• Conditions where morphine and opioids are contraindicated e.g. acute asthma, respiratory depression, acute alcoholism, head injuries, raised intra- cranial pressure and following biliary tract surgery.

• Co-codamol effervescent is not recommended for children under the age of 12 years.

• 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

• Monoamine oxidase inhibitor therapy, concurrent or within 14 days

4.4 Special warnings and precautions for use

Other paracetamol containing medication should not be taken when taking Co-codamol Effervescent Tablets.

This medicinal product contains 438mg sodium per tablet, equivalent to 22% of the WHO recommended maximum daily intake for sodium.

The maximum daily dose of this product is equivalent to 175% of the WHO recommended maximum daily intake for sodium.

Co-codamol Effervescent Tablets are considered high in sodium. This should be particularly taken into account for those on a low salt 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 severe liver or renal impairment. The hazards of overdose are greater in those with alcoholic liver disease.

Care should be taken when prescribing for elderly patients who can be more susceptible to the opioid effects such as CNS and gastro-intestinal effects.

Other susceptible patients include those on concurrent CNS depressant drugs, those with prostatic hypertrophy and those with inflammatory or obstructive bowel disorders.

Care should also be observed if prolonged therapy is contemplated.

Caution is advised when taking codeine with monoamine oxidase inhibitor (MAOI) therapy. Co-codamol Effervescent Tablets should not be taken concurrently or within 14 days of MAOI's.

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

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 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 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/DHC regularly for a long time can lead to addiction.

CYP2D6 metabolism

Codeine is p a r tia ll y 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 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 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 (including other opioid analgesics and alcohol) or other paracetamol containing products.

Paracetamol may increase the elimination half-life of chloramphenicol. Oral contraceptives may increase its rate of clearance. There is increased absorption when taken with metoclopramide or domperidone. Co- administration with colestyramine may reduce absorption.

Patients on anticoagulants may take occasional doses of Co-codamol Effervescent Tablets but the anticoagulant effect of warfarin and coumarins may be enhanced by prolonged regular administration of paracetamol with increased risk of bleeding. Occasional doses have no significant effect.

Concurrent use with centrally acting muscle relaxants may increase the risk of respiratory depression.

Concurrent use of MAO inhibitors or tricyclic antidepressants with codeine may increase the effect of either the antidepressant or codeine. Concurrent use of anticholinergic and codeine may produce paralytic ileus.

MAOI's taken with pethidine have been associated with severe CNS excitation or depression (including hypertension or hypotension). Although this is not been documented with codeine, it is possible that a similar interaction may occur and therefore the use of codeine should be avoided while the patient is taking MAOIs and for 2 weeks after MAOI discontinuation.

Enzyme-inducing medicines, such as some antiepileptic drugs (phenytoin, phenobarbital, carbamazepine) have been shown in pharmacokinetic studies to reduce the plasma AUC of Paracetamol to approximately 60%. Other substances with enzyme inducing properties, e.g. rifampicin and St. John's wort (hypericum) are also suspected of causing lowered concentrations of Paracetamol. In addition, the risk of liver damage during treatment with maximum recommended doses of Paracetamol will be higher in patients being treated with enzyme-inducing agents.

4.6 Pregnancy and lactation

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

A large amount of data on pregnant women indicates neither malformation, 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.

As a precautionary measure, use of Co-codamol should be avoided during the third trimester of pregnancy and during labour.

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.

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.

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 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

4.8 Undesirable effects

Reported adverse reactions seem more prominent in ambulatory than non- ambulatory patients and some of these effects may be alleviated if the patient lies down.

Adverse effects of paracetamol are rare.

A tabulated list of adverse reaction is outlined below:

System Organ Class

Adverse Effects (Fequency not known)

Blood and lymphatic system disorders

Thrombocytopenia, agranulocytosis

Immune system disorders

Anaphylactic reaction, hypersensitivity

Psychiatric disorders

Dysphoria, euphoria, confusion

Nervous System disorders

Dizziness, sedation, headache, drowsiness

Ear and Labyrinth disorders

Deafness

Respiratory thoracic and mediastinal disorders

Bronchospasm, dyspnoea

Gastro-intestinal disorders

Nausea, vomiting, constipation, abdominal pain, pancreatitis.

Renal and urinary disorders

Urinary retention

Skin and subcutaneous tissue disorders

Pruritus, rash, urticarial, fixed drug eruption, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis, angioedema.

1 Deafness has been reported in patients after long term use of high doses of codeine – Paracetamol.

2 Drug-induced pancreatitis associated with Paracetamol has been reported in literature to be a rare reaction only occurring in patients taking in excess of the recommended doses. Literature reports have also associated cases of pancreatitis with codeine.

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

In clinical use of Paracetamol-containing products, there have been a few reports of blood dyscrasias including thrombocytopenia and agranulocytosis but these were not necessary causally related to Paracetamol.

Very rare cases of serious skin reactions have been reported.

Co-codamol Effervescent Tablets are generally well tolerated but hypersensitivity reactions including skin rashes may occur. Rare cases of anaphylaxis, angioedema, urticaria, pruritus and fixed drug eruption have been reported with medications containing paracetamol and/or codeine.

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 vomiting, constipation, nausea, light-headedness, dizziness, confusion, drowsiness and 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/DHC 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.

Tolerance and dependence can occur, especially with prolonged high dosage of codeine.

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 10g or more of paracetamol. Ingestion of 5g or more or paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk factors

Risk factors

If the patient

a. Is on long term treatment with carbamazepine, phenobarbital, 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 overdose in the first 24 hours are pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Also increased levels of hepatic transaminases, lactate dehydrogenase and bilirubin with a reduction in prothrombin level may appear. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, gastrointestinal bleeding 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 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 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 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

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

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

Sodium hydrogen carbonate

Citric acid anhydrous

Sodium carbonate

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 the original package.

6.5 Nature and contents of container

Blister Strips: 41 g/sqm Glassine Paper / 17.25 g/sqm Polyethylene Foil / 9 micron Aluminium foil / 35.50 g/sqm Polyethylene Foil assembled into an outer carton.

Pack sizes: 30, 32, 56, 60, 84, 90 and 100 tablets.

6.6 Special precautions for disposal and other handling

None

7. Marketing authorisation holder

Fannin (UK) Limited

DCC Vital,

Westminster Industrial Estate,

Repton Road, Measham

Swadlincote,

Derbyshire,

England

DE12 7DT

8. Marketing authorisation number(s)

20417/0025

9. Date of first authorisation/renewal of the authorisation

22 October 2002 / 18 May 2009

10. Date of revision of the text

30 September 2019