SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Co-Codamol 30 mg/500 mg Effervescent Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each effervescent tablet contains:

Paracetamol 500.0mg

Codeine Phosphate Hemihydrate 30.0mg

Excipients: sorbitol (E420)

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Effervescent Tablet

White, bevelled, flat, round tablets.

4.1.    Therapeutic indications

For the relief of severe pain in adults.

Codeine is indicated in children older than 12 years of age for the treatment of acute moderate pain which is not relieved by other analgesics such as paracetamol or ibuprofen (alone).

4.2.    Posology and method of administration

Co-codamol 30 mg/500 mg Effervescent Tablets are given orally and should be dissolved in at least half a tumbler-full of water before taking.

Codeine 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 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: The dose is one or two effervescent tablets at intervals of not less than 6 hours between doses, 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.

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

Paediatric population Children aged 12 years and older:

The recommended codeine dose for children 12 years and older should be 30 to 60 mg every 6 hours when necessary up to a maximum dose of 240 mg daily (based on 0.5-1 mg/kg).

Children aged below 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).

4.3. Contraindications

Cocodamol 30 mg/500 mg Effervescent Tablets are contraindicated:

•    In patients with known hypersensitivity to paracetamol or codeine which is rare, or hypersensitivity to any of the other constituents

• In patients with conditions where morphine and opioids are contraindicated e.g., acute asthma, respiratory depression, acute alcoholism, head injuries, raised intra-cranial pressure, where there is risk of paralytic ileus and following biliary tract surgery; monoamine oxidase inhibitor therapy, concurrent or within 14 days

• In all paediatric patients (0 to 18 years of age) that 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 from whom it is known that they are CYP2D6 ultra-rapid metabolisers

4.4 Special warnings and precautions for use

Each tablet contains 410mg sodium (17.83mEquivalents). This sodium content should be taken into account when prescribing for patients in whom sodium restriction is indicated.

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 ultrarapid 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 nausea, vomiting, constipation, lack of appetite, somnolence, shallow breathing, small pupils and confusion. 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.

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 MAOIs or within 14 days of stopping MAOIs (see section 4.5).

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.

As this medicine contains sorbitol, patients with rare hereditary problems of fructose intolerance should not take this medicine.

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

Caution is advised in patients with underlying sensitivity to aspirin and/or to nonsteroidal anti-inflammatory drugs (NSAIDs).

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 pain killer 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.

The leaflet will state in the “pregnancy and breast-feeding” subsection of the section 2 “Before taking your medicine”:‘Do not take this medicine if you are breast-feeding your baby”

4.5. Interactions with other medicinal products and other forms of interaction

Metoclopramide/Domperidone: The speed of absorption of paracetamol may be increased by metoclopramide or domperidone. Opioid analgesics such as codeine antagonize the effects of metoclopramide and domperidone on the gastrointestinal tract.

Oral anticoagulants: 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.

Cholestyramine: Absorption of paracetamol may be reduced by cholestyramine.

Oral contraceptives Oral contraceptives may increase the rate of clearance of paracetamol.

Chloramphenicol: Paracetamol may increase the elimination half-life of chloramphenicol.

CNS depressants: The hypotensive and sedative effects of CNS depressants (including other opioid analgesics, tricyclic antidepressants, antipsychotics, anxiolytics, hypnotics and alcohol) may be potentiated by codeine.

Monoamine oxidase inhibitors (MAOIs): MAOIs taken with pethidine have been associated with severe CNS excitation or depression (including hypertension or hypotension). Although this has 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.

Sodium oxybate: Concomitant use of sodium oxybate (gamma hydroxybutyrate, GHB) should be avoided as opioids enhance the effects of this substance.

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. There is a risk of gastric stasis and of inhalation pneumonia in mothers during labour.

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

Breast - feeding

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 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 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

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:

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

Summary of Safety Profile

Codeine can produce typical opioid effects including gastrointestinal and CNS effects; 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.

Adverse effects of paracetamol are rare. There have been reports of blood dyscrasias, but these were not necessarily causally related to paracetamol.

Tabulated list of adverse effects

Post-Marketing experience

The following terms and frequencies are applied: 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),

Where frequency cannot be estimated from clinical trials data, it is recorded as “Not known”.

System Organ Class	Adverse Effect	Frequency
Blood & lymphatic system disorders	Thrombocytopenia Neutropenia Leucopenia	Very rare
	Agranulocytosis	Not known
Immune system disorders	Hypersensitivity reactions, including rash Angioedema	Not known

	Anaphylactic shock
Metabolism & nutrition disorders	Decreased appetite	Not known
Psychiatric disorders	Confusional state Restlessness* Irritability* Drug dependence	Not known
Nervous system disorders	Dizziness Light headedness Drowsiness	Not known
Eye disorders	Miosis	Not known
Gastrointestinal disorders	Constipation Nausea Vomiting	Not known
	Pancreatitis	Very rare
Skin & subcutaneous tissue disorders	Angioedema Rash Urticaria Pruritus Fixed drug eruption.	Not known
	Serious skin reactions	Very rare
Renal & urinary disorders	Urinary retention	Not known
Respiratory, thoracic and mediastinal disorders	Bronchospasm	Not Known
General disorders	Drug tolerance	Not known

*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

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

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 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 350mg of codeine or a child more than 5mg/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 4 hours after ingestion, or 8 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, 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 48 hours 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 remote 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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anilides, Paracetamol combinations ATC Code: NO2B E51

Mechanism of action

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 these receptors, and its analgesic effect is due to its conversion to morphine.

Clinical efficacy and safety

Codeine, particularly in combination with other analgesics such as paracetamol, has been shown to be effective in acute nociceptive pain.

5.2 Pharmacokinetic properties Absorption

Following oral administration of two effervescent tablets (i.e., a dose of paracetamol 1000mg and codeine 60mg) the mean maximum plasma concentrations of paracetamol and codeine were 20.4pg/ml and 218.8ng/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 50.0pg/ml per hour for paracetamol and 450.0ng/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.

Biotransformation

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.

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.

Elimination

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%).

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

Tablet

Sodium hydrogen carbonate Anhydrous sodium carbonate Anhydrous citric acid Sodium docusate Sorbitol (E420)

Saccharin sodium Dimeticone Sodium benzoate Macrogol 6000

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

2 years.

6.4    Special precautions for    storage

Do not store above 25°C. Store in the original package in order to protect from moisture and light.

6.5    Nature and contents of container

Aluminium/polyethylene blister strips (30 micron aluminium strip with internal polyethylene coating) containing 4 or 10 tablets per strip in an outer cardboard carton. Pack sizes of 28, 30, 50, 56 and 100.

White polypropylene tubes sealed with a polyethylene stopper containing a desiccant cartridge in an outer cardboard carton. Tube sizes of 8, 10 and 16 tablets. Pack sizes of 10, 16, 32 and 96 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Manx Pharma Limited Taylor Group House Wedgnock Lane Warwick CV34 5YA United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 15833/0025

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/09/2007

10    DATE OF REVISION OF THE TEXT

14/07/2016