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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Co-Codamol Effervescent Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each effervescent tablet contains:

Paracetamol	500.0mg
Codeine phosphate	8.0mg

For a full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Effervescent tablets.

The tablets are white, round and flat with a bevelled edge and rough surface.

4    CLINICAL PARTICULARS

4.1 Therapeutic indications

For the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone such as headache, migraine, neuralgia, toothache, rheumatic, muscular and period pains.

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:

One or two tablets to be taken every four hours if necessary. Do not exceed 8 tablets in 24 hours.

Paediatric population:

Children aged 12 years to 18 years:

One or two tablets to be taken every 6 hours when necessary. Do not exceed 8 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 section 4.3 and 4.4)

Elderly patients:

Normal adult dose unless there is impaired kidney or liver function.

Directions:

The tablets must be dissolved in half a glass of water (100ml). The tablets dissolve more quickly in warm water or if stirred.

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.

4.3 Contraindications

Caution should be taken in patients with impaired kidney or liver function; previous hypersensitivity to paracetamol, codeine or other ingredients; acute respiratory depression; acute alcoholism and risk of paralytic ileus; raised intracranial pressure; or head injury.

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 patient for whom it is known they are CYP2D6 ultra-rapid metabolisers.

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:

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

The label will state:

Front of pack

Can cause addiction

For three days use only Back of pack

For pain relief from headache, migraine, neuralgia, toothache, rheumatic, muscular and period pains.

If you need to take this medicine continuously for more than three days you should see your doctor or pharmacist.

This medicine contains codeine which can cause addiction if you take it continuously for more than three days. If you take this medicine for headaches for more than three days it can make them worse.

Do not exceed the stated dose.

This product contains paracetamol.

Do not take with any other paracetamol-containing products.

The leaflet will state:

Headlines section (to be prominently displayed)

This medicine can only be used for relieve of acute moderate pain including headache, migraine, neuralgia, toothache, rheumatic, muscular and period pains.

You should only take this product for a maximum of three days at a time. If you need to take it for longer than three days you should see your doctor or pharmacist for advice.

This medicine contains codeine which can cause addiction if you take it continuously for more than three days. This can give you withdrawal symptoms from the medicine when you stop taking it

If you take this medicine for headaches for more than three days it can make them worse

Section 1: What Co-codamol effervescent tablets are and what they are used for

•    Co-codamol effervescent tablets contain the active ingredients paracetamol and codeine. Co-codamol effervescent tablets are for the short term treatment of acute moderate pain including headaches, migraine, neuralgia, toothache, rheumatic, muscular and period pain when other painkillers have not worked.

Section 2: Before you take Co-codamol effervescent tablets

•    This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days. This can give you withdrawal symptoms from the medicine when you stop taking it

•    If you take a painkiller for headaches for more than 3 days it can make them worse Section 3: How to take Co-codamol effervescent tablets

•    Do not take for more than 3 days. If you need to use this medicine for more than 3 days you must speak to your doctor or pharmacist

Possible withdrawal effects when stopping treatment

This medicine contains codeine and can cause addiction if you take it continuously for more than three days. When you stop taking it you may get withdrawal symptoms. You should talk to your doctor or pharmacist if you think you are suffering from withdrawal symptoms

Section 4: Possible side effects

Some people may have side effects when taking this medicine. If you have any unwanted side-effects you should seek advice from your doctor, pharmacist or other healthcare professional. Also you can help to make sure that medicines remain as safe as possible by reporting unwanted side effects via the internet at www.mhra.gov.uk/yellowcard, alternatively you can call Freephone 0808 100 3352 (available between 10am -2pm Monday - Friday) or fill in a paper form available from your local pharmacy.

This will appear at the end of section 4 How do I know if I am addicted?

If you take the medicine according to the instructions on the pack it is unlikely that you will become addicted to the medicine. However, if the following apply to you it is important that you talk to your doctor:

•    You need to take the medicine for longer periods of time

•    You need to take more than the recommended dose

•    When you stop taking the medicine you feel very unwell but you feel better if you start taking the medicine again

Patients who are pregnant should consult their doctor before taking this preparation. Keep out of the reach and sight of children.

Each tablet contains 438.0mg (19.1 millimoles) of sodium. This sodium should be taken into account when prescribing for patients on a sodium restricted diet.

Patients should be advised to seek immediate medical advice in the event of an overdose, even if they feel well.

Dependence can develop with repeated use of codeine and therefore withdrawal symptoms may appear if the product is withdrawn abruptly.

Care is advised in the administration of paracetamol-containing products to patients with severe renal or severe hepatic impairment and in those with noncirrhotic alcoholic liver disease. The hazards of overdose are greater in those with alcoholic liver disease. Care is also advised in patients with hypotension, hypothyroidism, convulsive disorders, asthma (avoid during an attack), prostatic hypertrophy.

4.5 Interaction with other medicinal products and other forms of interaction

i)	Alcohol, barbiturates, anticonvulsants and tricyclic antidepressants may increase the hepatotoxicity of paracetamol, particularly after an overdose.
ii)	chloramphenicol - paracetamol may increase the half-life of chloramphenicol.
iii)	colestyramine - may reduce absorption of paracetamol.
iv)	metoclopramide and domperidone- may potentiate the effect of paracetamol.
v)	the anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding.
vi)	Alcohol, antipsychotics, anxiolytics and hypnotics may enhance the sedative and hypotensive effects of codeine.
vii)	There may be reduced plasma-ciprofloxacin concentrations if ciprofloxacin is administered with codeine.
viii)	MAOIs- codeine may cause a hypotensive or hypertensive effect if used with MAOIs. Concomitant use should be avoided and codeine should not be administered until 2 weeks after MAOI discontinuation.
ix)	Cisapride, metoclopramide, domperidone - if administered with codeine may lead to antagonism of gastrointestinal effects
x)	Cimetidine may inhibit the metabolism of opiates
xi)	The plasma concentration of codeine may be increased by ritonavir.

4.6 Fertility, pregnancy and lactation

There is inadequate evidence for the safety of codeine in 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 giving co-codamol tablets to pregnant mothers particularly during the first trimester.

Paracetamol has been detected in breast milk, although it is estimated that less than 0.1% of the maternal dose appears in 100ml of breast milk. Codeine has also been shown to be excreted in breast milk, although the quantity was not determined.

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

Codeine can occasionally cause drowsiness, if affected the patient should not drive or operate machinery. Other drugs including alcohol may enhance the drowsiness caused by codeine (see 4.5).

4.8. Undesirable Effects

If given in therapeutic doses side effects are very rare. Haematological reaction, thrombocytopenia, agranulocytosis and acute pancreatitis, after prolonged use, have been reported. Skin rashes and other allergic reactions may occur occasionally. Most reports of adverse reactions to paracetamol relate to overdosage with the drug particularly liver damage and, less frequently, renal damage. Codeine can cause constipation, nausea, drowsiness, confusion and vomiting. Larger doses may produce respiratory depression and hypotension. Other side-effects include difficulty with micturition, uretic or billiary spasm, dry mouth, sweating, headache, facial flushing, vertigo, bradycardia, tachycardia, palpitations, postural hypotension, hypothermia, hallucinations, dysphoria, mood changes, dependence, miosis, decreased libido or potency, rashes, urticaria and pruritis.

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

Codeine

The effects of Codeine 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 coingested, 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.

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, 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 eg 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 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypogylycaemia, 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 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Paracetamol combinations excl. Psycholeptics ATC code: NO2BE51

Analge sic/antipyretic.

Codeine is a centrally acting weak analgesic. Codeine exerts its effect 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: Paracetamol is rapidly absorbed from the upper gastrointestinal tract after oral administration.

Peak plasma levels of 15-20 micrograms per ml after 1g oral dose occur within 30-90 minutes, depending on dosage form. It is rapidly distributed throughout the body and is primarily metabolised in the liver. About 85% is by conjugation with glucuronide and sulphate and about 10% by conjugation with glutathione.

Excretion of the biotransformation products is via the kidney. The elimination half-life is approximately 2-3 hours.

In overdose glucuronide pathways become saturated and excess paracetamol is metabolised via the glutathione pathway. Hepatic glutathione is rapidly depleted and an intermediate hydroxylamine metabolite accumulates and binds to liver proteins causing irreversible damage.

Codeine: Codeine is rapidly absorbed from the gastro-intestinal tract following oral administration. Peak plasma levels are achieved in about 1 hour following oral ingestion and the half-life in plasma is about 2-4 hours.

Codeine is metabolised in the liver by 0- and N-demethylation to morphine norcodeine, normorphine, hydrocodone and other metabolites. Approximately 10% of a dose of codeine is converted to morphine and accounts for most of the analgesic effect.

Urinary excretion is the main route of elimination of codeine and its metabolites which are mostly excreted as glucuronide conjugates.

5.3 Preclinical safety data

Paracetamol:

Acute Toxicity: Paracetamol hepatotoxicity is directly dependent on the plasma concentration related to time. Plasma concentrations above 1.2mmol/l at 4 hours, 0.6mmol/l at 8 hours and 0.3mmol/l at 12 hours are criteria for treatment with acetylcysteine to prevent irreversible liver damage.

Chronic Toxicity: In animal experiments the subchronic and chronic toxicity of paracetamol occurred in rats and mice as lesions in the gastro-intestinal tract, blood-count changes, degeneration and even necrosis of the hepatic and renal parenchyma. The metabolites that are assumed to have the toxic effects and the organic changes associated with them have been proven in humans as well.

Therefore, paracetamol should not be taken for a long period of time and in excessive doses. Oral daily doses with clearly hepatotoxic effects are around 5.8g for non-alcoholics, symptoms of intoxication can occur as soon as 3 weeks after administration.

Mutagenic and tumorigenic potential: In mammalian cell cultures paracetamol induces chromosome mutations depending on its concentration. In-vivo tests show negative as well as slightly positive results. Due to the insufficient relevance of the most part of the in-vivo tests no final evaluation is possible at this time.

Long-term studies in rats and mice have yielded no indications of a carcinogenic effect.

Reproductive toxicology: Paracetamol passes the placental barrier. Animal studies and experience to date in humans reveal no evidence of embryotoxicity.

Codeine:

Acute Animal Toxicity

LD50 values for mice, rabbits and rats using different methods of administration are as follows:

	LD50 (mg kg-1)
	Mice	Rabbits	Rats
Intravenous	ranges from	55-70
Oral	400	120	500

Intraperitoneal

approximately 100

Reproductive Toxicology

There is no information on the carcinogenic or teratogenic potential of codeine in animal species. From studies, it has been reported that children born to mothers exposed to narcotic analgesics during months 1-4 of their pregnancy, may show a possible link between codeine exposure and respiratory malformations.

Codeine is excreted in the breast milk of nursing mothers. It has been reported that respiratory malformation in neonates may be associated with codeine exposure during pregnancy.

Clinical Toxicity

It is difficult to state an exact amount of an opioid product that would be toxic or fatal to man because chronic administration may lead to the development of tolerance. Serious toxicity has been reported in non-tolerant individuals following oral ingestion of 40mg-60mg methadone. Older literature suggests that a normal healthy adult will not die after a 120mg oral dose of morphine, or suffer from serious toxicity with less than a parenteral dose of 30mg.

Caution should be employed in the treatment of patients with liver or kidney disease as under these conditions the pharmacokinetics of drug metabolism are significantly altered. This may lead to increased bioavailability and cumulative effects.

Morphine-like opioids should also be used with caution in patients with:

-    reduced blood volume as these agents can aggravate hypovolaemic shock.

-    reduced respiratory reserve as further depressant effects may occur.

As the dose is increased, the toxic effects, including respiratory depression become more pronounced. It has been reported that in acute overdosage producing respiratory depression, hypotension, circulatory failure and deepening coma, blood concentrations of codeine ranged from 1.4 to 5.6mg/l.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Citric acid anhydrous

Povidone

Sodium saccharin

Sodium bicarbonate

Sodium carbonate anhydrous

Simethicone

Polysorbate 80

Aspartame.

6.2 Incompatibilities

None known.

6.3 Shelf life

24 months.

6.4 Special precautions for storage

Do not store above 25^oC

Store in the original package in order to protect from moisture

6.5 Nature and contents of container

Strip pack using PPFM laminate constructed of:

40gsm MGBK paper

16gsm LDPE

9p aluminium foil

34.5gsm LDPE.

Strips are packed into an outer carton.

Pack sizes: 10, 12, 16, 24, 30, 32, (P)

6.6 Special precautions for disposal

None

7 MARKETING AUTHORISATION HOLDER

Ennogen Pharma Limited Unit G4,

Riverside Industrial Estate,