This information is intended for use by health professionals

1. Name of the medicinal product

Co-codamol 30 mg/500 mg effervescent tablets.

2. Qualitative and quantitative composition

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

Excipients with known effects:

Each effervescent tablet contains 5 mg of aspartame

Each effervescent tablet contains 438 mg of sodium.

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

For the relief of severe pain.

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).

4.2 Posology and method of administration

Posology

Co-codamol should be used at the lowest effective dose for the shortest period of time. This dose may be taken, up to 4 times a day at intervals of not less than 6 hours. Maximum daily dose of codeine should not exceed 240 mg.

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

Two tablets dissolved in water not more frequently than every 4 hours, up to a maximum of 8 tablets in any 24-hour period.

Elderly

As adults, however a reduced dose may be required (see section 4.4).

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.

Paediatric population

Children aged 12 years to 15 years:

The recommended Co-codamol dose for children 12 years old to 15 years old is 1 tablet dissolved in water every 6 hours when necessary up to a maximum of 4 tablets in 24 hours.

Children aged 16 years to 18 years:

The recommended Co-codamol dose for children 16 years old to 18 years is one to two tablets dissolved in water every six hours when necessary up to a maximum of eight tablets in any 24 hour period.

Children aged less than 12 years:

Co-codamol 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).

Method of administration

Co-codamol is for oral administration.

The tablets should be dissolved in at least half a glass of water before taking.

4.3 Contraindications

• Hypersensitivity to codeine or paracetamol or to any of the excipients listed in section 6.1.

• 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

• Condition where morphine and opioids are contraindicated e. g:

o acute asthma,

o respiratory depression,

o acute alcoholism,

o head injuries,

o raised intra-cranial pressure

o following biliary tract surgery,

o breast-feeding (see section 4.6).

• In patients currently receiving or within 14 days of stopping monoamine oxidase inhibitor therapy.

4.4 Special warnings and precautions for use

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

These tablets contain 438 mg sodium per tablet and should be avoided by patients on a low sodium 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 depressent drugs, those with prostatic hypertrophy and those with inflammatory or obstructive bowel disorders.

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 partially metabolised by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme they will not obtain adequate analgesic effect. 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 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

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

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.

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

4.6 Fertility, pregnancy and lactation

Pregnancy

There is inadequate evidence of the safety of codeine in human pregnancy, but there is epidemiological evidence for the safety of paracetamol. Both substances have been used for many years without apparent ill consequences and animal studies have not shown any hazard. Careful consideration should be given before prescribing the medicinal 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 indicate neither malformative, nor feto/neonatal toxicity. Paracetamol can be used during pregnancy if clinically needed 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 labor.

Breast-feeding

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

Codeine should not be used during breast-feeding (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 metabolites, 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

Patients should be warned not to drive or operate machinery if they become dizzy or sedated while taking Co-codamol.

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

Adverse effects of paracetamol are rare:

Blood and lymphatic system disorders

Very rare: thrombocytopenia, neutropenia, leucopenia

Not known: agranulocytosis

Immune system disorders

Hypersensitivity including skin rash may occur.

Not known: Anaphylactic shock, angioedema.

Respiratory, thoracic and mediastinal disorders

Not known: bronchospasm (see section 4.4)

Skin and subcutaneous disorders

Very rare cases of serious skin reactions such as Stevens - Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP).

Very rare occurrence of pancreatitis.

Codeine may sometimes cause typical opioid effects such as:

Gastrointestinal disorders

Not known: Vomiting, constipation, nausea, abdominal pain.

Nervous system disorders

Not known: Light-headedness, headache, dizziness, confusion, drowsiness

Renal and urinary disorder

Not known: Urinary retention.

The frequency and severity are determined by dosage, duration of treatment and individual sensitivity. Tolerance and dependence can occur, especially with prolonged high dosage of codeine.

• 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.

• Long-term usage of high doses of codeine + paracetamol can be rarely associated with ototoxicity leading to sensorineural hearing loss.

• 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

Paracetamol

Liver damage is possible in adults who have taken 10 g or more of paracetamol. Ingestion of 5 g 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, phenobarbital, phenytoin, primidone, rifampicin, St John's Wort or other medicinal products 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. Increased levels of hepatic transaminases, lactate dehydrogenase and bilicubin may occur and the INR may increase. 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, pancreatitis and pancytopenia 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 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 of codeine over-dosage 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 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

Pharmacotherapeutic group: Anilides, Paracetamol combinations

ATC Code: NO2B E51

Paracetamol is an analgesic which acts peripherally, probably by blocking impulse generation at the bradykinin sensitive chemo-receptors 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 paracetamol's lack of appreciable anti-inflammatory activity. Paracetamol also exhibits antipyretic 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

Following oral administration of two effervescent tablets (i.e., a dose of paracetamol 1000 mg and codeine 60 mg) the mean maximum plasma concentrations of paracetamol and codeine were 20.4 μg/ml and 218.8 ng/ml respectively. The mean times to maximum plasma concentrations were 0.34 hours for paracetamol and 0.42 hours for codeine phosphate.

The mean AUC for the 10 hours following administration was 50.0 μg/ml per hour for paracetamol and 450.0 ng/ml per hour for codeine.

The bioavailabilities of paracetamol and codeine phosphate when given as the combination are similar to those when they are given separately.

Codeine is mainly metabolized by glucuronidation to codeine-6-glucuronide. Minor routes of metabolism include O-demethylation leading to morphine, N-demethylation to norcodeine and after both O-and N-demethylation formation of normorphine. Morphine and norcodeine are further transformed in glucuroconjugates. Unchanged codeine and its metabolites are mainly excreted by urinary route within 48h (84.4±15.9%).

The O-demethylation of codeine to morphine is catalyzed by the cytochrome P450 isozyme 2D6 (CYP2D6) which shows genetic polymorphism that may affect the efficacy and toxicity of codeine.

Genetic polymorphism in CYP2D6 leads to ultra-rapid, extensive and poor metaboliser phenotypes.

5.3 Preclinical safety data

There are no preclinical data of relevance which are additional to that already included in other sections of the SPC.

6. Pharmaceutical particulars
6.1 List of excipients

Sodium hydrogen carbonate,

Citric acid anhydrous,

Sodium carbonate anhydrous,

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

Aluminium / Aluminium foil strips

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

6.6 Special precautions for disposal and other handling

Co-codamol Effervescent Tablets should be dissolved in half a tumbler full of water before taking.

7. Marketing authorisation holder

Cipla (EU) Limited,

Dixcart House, Addlestone Road,

Bourne Business Park, Addlestone,

Surrey, KT15 2LE, United Kingdom.

8. Marketing authorisation number(s)

PL 36390/0006

9. Date of first authorisation/renewal of the authorisation

06/10/2011

10. Date of revision of the text

23/03/2018.