SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Co-codamol 30/500 Effervescent Tablets.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 500mg paracetamol and 30mg codeine phosphate hemihydrate. Excipients with known effect:

Each tablet contains 50mg of sorbitol and 10mg of saccharin sodium.

For the full list of excipients, see section 6.1

3.    PHARMACEUTICAL FORM

Effervescent Tablets.

White bevelled-edge tablets, scored on one face.

4.1    Therapeutic indications

For the relief of severe 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 Posology

Adults:    Two tablets not more frequently than every 4 hours, up to a

maximum of 8 tablets in any 24 hour period.

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

warnings.

Paediatric population

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 section 4.3 and 4.4).

Method of administration

For oral administration.

4.3 Contraindications

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

•    Conditions where morphine and opioids are contraindicated eg, acute asthma, respiratory depression, acute alcoholism, head injuries, raised intra-cranial pressure and following biliary tract surgery; monoamine oxidase inhibitor therapy, concurrent or within 14 days.

•    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

4.4 Special warnings and precautions for use

Each tablet of the soluble formulation contains 388mg sodium (16.87mEquivalents). This sodium content should be taken into account when prescribing for patients in whom sodium restriction is indicated.

Care should be observed in administering the product to any patient whose condition may be exacerbated by opioids, particularly the elderly, who may be sensitive to their central and gastro-intestinal effects, 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.

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 alcoholic liver disease.

Patients should be advised not to exceed the recommended dose and not take other paracetamol containing products concurrently.

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

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.

CYP2D6 metabolism

Codeine is metabolised by 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 population are summarised below:

Population	Prevalence %
Afri can/Ethi opi an	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 postoperatively 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 Interactions with other medicinal products and other forms of interaction

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.

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.

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

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. Nonetheless careful consideration should be given before prescribing the products 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.

Breastfeeding

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

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 to use machines

Patients should be advised not to drive or operate machinery if affected by dizziness or sedation.

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:

-    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

•    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.

The information below lists reported adverse reactions, ranked using the following frequency classification:

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

Codeine can produce typical opioid effects including constipation, nausea, vomiting, dizziness, light-headedness, confusion, drowsiness and 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.

There have been very rare occurrences of pancreatitis.

Immune system disorders

Hypersensitivity including skin rash may occur.

Blood and the lymphatic system

Not known: blood dyscrasias including thrombocytopenia and agranulocytosis

Skin and subcutaneous tissue disorders

Very rare cases of serious skin reactions have been reported

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

Nausea and vomiting are prominent symptoms of codeine toxicity and if there is evidence of circulatory and respiratory depression, suggested treatment is gastric lavage and catharsis. If CNS depression is severe, assisted ventilation, oxygen and parenteral naloxone may be needed.

Patients in whom oxidative liver enzymes have been induced, including alcoholics and those receiving barbiturates and patients who are chronically malnourished, may be particularly sensitive to the toxic effects of paracetamol in 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, gastrointestinal bleeding, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Liver damage is likely in adults who have taken 10g or more of paracetamol. It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested), become irreversibly bound to liver tissue.

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 and any patient who had ingested around 7.5g or more of paracetamol in the preceding 4 hours should undergo gastric lavage. Administration of oral methionine or intravenous N-acetylcysteine, which may have a beneficial effect up to at least 48 hours after the overdose, may be required. General supportive measures must be available.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Paracetamol, combinations excl. Psycholeptics ATC Code: N02B 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 p opioid receptors, although codeine has low affinity for those 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 (ie, a dose of paracetamol 1000mg and codeine phosphate 60mg) the mean maximum plasma concentrations of paracetamol and codeine were 20.4 pg/ml and 218.8ng/ml respectively. The mean times to maximum plasma concentrations were 0.34 hours for paracetamol 0.42 hours for codeine phosphate.

The mean AUC for the 10 hours following administration was 50.0pg.ml ^-1.h for paracetamol and 450.0 ng/ml ^-1.h for codeine.

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

5.3 Preclinical safety data

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

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium bicarbonate, anhydrous citric acid, anhydrous sodium carbonate, sorbitol powder, saccharin sodium, povidone, dimethicone, sodium lauryl sulphate.

6.2    Incompatibilities

Not applicable

6.3    Shelf life

4 years in PPFP strips 3 years in Surlyn laminate strips.

6.4. Special Precautions for Storage

Do not store above 25°C. Store in the original package.

6.5 Nature and contents of container

PPFP strips in cardboard cartons.

Pack sizes: 4, 12, 30, 60 and 100 tablets.

Surlyn laminate strips in cardboard cartons.

Pack sizes: 4, 12, 30, 60 and 100 tablets.

6.6    Special precautions for disposal

No special requirements

7    MARKETING AUTHORISATION HOLDER

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

Trading as

Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS Or

Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK 8. MARKETING AUTHORISATION NUMBER

PL 17780/0046

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

04/03/2009

10 DATE OF REVISION OF THE TEXT

01/08/2016