This information is intended for use by health professionals

1. Name of the medicinal product

Co-codamol 8mg/500mg Effervescent Tablets

2. Qualitative and quantitative composition

Co-codamol 8mg/500mg Effervescent Tablets contain:

Paracetamol 500mg

Codeine Phosphate Hemihydrate 8mg

Excipients with known effect:

Each tablet contains 418.5 mg sodium and 100 mg of sorbitol

For the full list of excipients, see section 6.1

3. Pharmaceutical form

Effervescent Tablets

White to off white round, flat, bevelled edge tablets, plain on both sides.

4. Clinical particulars
4.1 Therapeutic indications

1) Co-codamol 8mg/500mg Effervescent Tablets is indicated in children 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).

2) As an antipyretic.

4.2 Posology and method of administration

Posology

Co-codamol 8mg/500mg Effervescent Tablets 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.

Adults: 1-2 tablets which may be repeated every 6 hours. Do not take more than 8 tablets in any 24 hour period.

Paediatric population:

Children aged 16-18 years: 1-2 tablets every 6 hours when necessary up to a maximum of 8 tablets in 24 hours.

Children aged 12 years to 15 years: The recommended Co-codamol 8mg/500mg Effervescent Tablets dose for children 12-15 years should be 1 tablet which may be repeated every 6 hours when necessary up to a maximum dose of 4 tablets in any 24 hour period.

Children aged less than 12 years: Co-codamol 8mg/500mg Effervescent Tablets 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: Dosage should be reduced in the elderly where there is impairment of hepatic function.

For oral administration.

Directions

The tablets must be dissolved in half a glass of water. The tablets dissolve more quickly in warm water, or if stirred.

Prior to starting treatment with opioids should be held with patients to put in place a strategy for ending treatment with codeine phosphate hemihydrate and paracetamol in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

4.3 Contraindications

• Diarrhoea caused by poisoning until the toxic material has been eliminated, or diarrhoea associated with pseudomembraneous colitis

• Respiratory depression

• Obstructive airways disease

• 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 that they are CYP2D6 ultra-rapid metabolisers.

• This product contains 418.5 mg of sodium per effervescent tablet. This may be harmful to people on a low sodium or low salt diet.

• Hypersensitivity to Paracetamol, codeine phosphate hemihydrate or any excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Co-codamol 8mg/500mg Effervescent Tablets should be used with caution in patients with:

• hepatic function impairment (avoid if severe) and those with noncirrhotic

• alcoholic liver disease. The hazards of overdose are greater in those with alcoholic liver disease.

• prolonged use of Co-codamol 8mg/500mg Effervescent Tablets may cause hepatic necrosis.

• renal function impairment

• hypothyroidism (risk of depression and prolonged CNS depression is increased)

• inflammatory bowel disease risk of toxic megacolon

• opioids should not be administered during an asthma attack

• convulsions may be induced or exacerbated

• drug abuse, dependence (including alcoholism), enhanced instability, suicidal ideation or attempts predisposed to drug abuse

• head injuries or conditions where intracranial pressure is raised

• gall bladder disease or gall stones opioids may cause biliary contraction

• gastrointestinal surgery use with caution after recent GI surgery as opioids may alter GI motility

• prostatic hypertrophy or recent urinary tract surgery

• adrenocortical insufficiency, e.g. Addison's Disease

• hypotension and shock

• myasthenia gravis

• pheochromocytoma opioids may stimulate catecholamine release by inducing the release of endogenous histamine

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

Where analgesics are used long-term (>3 months) with administration every two days or more frequently, headache may develop or worsen. Headache induced by overuse of analgesics (MOH medication-overuse headache) should not be treated by dose increase. In such cases, the use of analgesics should be discontinued in consultation with the doctor.

This product contains 418.5 mg of sodium per effervescent tablet, equivalent to 20.93% of the WHO recommended maximum daily intake for sodium.

The maximum daily dose of this product is equivalent to 167.4% of the WHO recommended maximum daily intake for sodium.

Co-codamol 8mg/500mg Effervescent Tablets is considered high in sodium. This should be particularly taken into account for those on a low salt diet.

This product also contains sorbitol. Patients with hereditary fructose intolerance (HFI) should not take this medicinal product.

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 or very rarely fatal. Estimates of prevalence of ultra-rapid metabolisers in different populations are summarised 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%

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs:

Concomitant use of Co-codamol 8mg/500mg Effervescent Tablets and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Co-codamol 8mg/500mg Effervescent Tablets concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Paediatric population

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.

Label Warnings:

Do not take with any other paracetamol containing products.

Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage.

or if leaflet present:

Immediate medical advice should be sought in the event of an overdose, even if you feel well.

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

• Contains paracetamol.

• Do not take anything else containing paracetamol while taking this

• medicine.

• Talk to a doctor at once if you take too much of this medicine, even if you feel well.

Drug dependence, tolerance and potential for abuse

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance.

The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse, or addiction.

The clinical need for analgesic treatment should be reviewed regularly.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with codeine phosphate and paracetamol.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

4.5 Interaction with other medicinal products and other forms of interaction

Paracetamol can interact with the following:

• Drugs which alter gastric emptying time (eg cimetidine, ethyl alcohol, oral steroid contraceptives). These drugs reduce or delay peak paracetamol blood levels.

• Metoclopramide or domperidone increases the speed of absorption of paracetamol.

• Colestyramine reduces paracetamol absorption.

• Drugs which interfere with the metabolism of paracetamol by competition with metabolic pathways or substrates eg anticonvulsants (phenytoin), hepatic enzyme inducers, alcohol, barbiturates, tricyclic antidepressants. A poor diet (low protein) may also have a similar effect on the risk of serious paracetamol toxicity to hepatic enzyme inducers. Patients who have taken barbiturates, tricyclic antidepressants and alcohol may show diminished ability to metabolise large

doses of paracetamol, the plasma halflife of which may be prolonged.

• 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.

• Alcohol can increase the hepatotoxicity of paracetamol overdosage and may have contributed to the acute pancreatitis reported in one patient who had taken an overdosage of paracetamol.

Codeine Phosphate can interact with the following:

• CNS depressants enhanced sedative and/or hypotensive effect with alcohol, anaesthetics, hypnotics, anxiolytics, antipsychotics, hydroxyzine, tricyclic antidepressants

• Antibacterials, eg ciprofloxacin, avoid premedication with opioids as reduced plasma ciprofloxacin concentration

• MAOIs use only with extreme caution

• Cyclizine

• Mexiletine delayed absorption

• Metoclopramide and domperidone antagonise GI effects

• Cisapride possible antagonism of GI effects

• Dopaminergics (eg selegiline) possible risk of hyperpyrexia and CNS toxicity. This risk is greater with pethidine but with other opioids the risk is uncertain

• Ulcer healing drugs cimetidine inhibits the metabolism of opioid analgesics.

• Anticholinergics (eg atropine) risk of severe constipation which may lead to paralytic illness, and /or urinary retention

• Antidiarrhoeal drugs (eg loperamide, kaolin) increased risk of severe constipation

• Antihypertensive drugs (eg guanethidine, diuretics) enhanced hypotensive effect

• Opioid antagonists (eg buprenorphine, naltrexone, naloxone)

• Neuromuscular blocking agents additive respiratory depressant effects.

Sedative medicines such as benzodiazepines or related drugs:

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use.

Risk benefit must be considered because opioid analgesics cross the placenta. Studies in animals have shown opioids to cause delayed ossification in mice and increased resorption in rats.

Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.

Breastfeeding

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 ultrarapid 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 nonopioid analgesics prescribed. In severe cases consideration should be given to prescribing naloxone to reverse these effects.

Administration to nursing women is not recommended as codeine phosphate hemihydrate and paracetamol may be secreted in breast milk and may cause respiratory depression in the infant.

4.7 Effects on ability to drive and use machines

Opioid analgesics can impair mental function and can cause blurred vision and dizziness. Patients should make sure they are not affected before driving or operating machinery.

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

List of adverse reactions

The adverse reactions reported below are classified according to frequency of occurrence as follows: 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)

System Organ Class

Adverse Effects (Frequency not known)

Nervous system disorders

Not Known:

Drowsiness, impaired mental functions, confusion, vertigo, dizziness, changes in mood, hallucinations, CNS excitation (restlessness/excitement), convulsions, mental depression, headache, trouble sleeping, or nightmares, raised intracranial pressure, tolerance or dependence.

Psychiatric disorders

Not Known:

Drug dependence (see section 4.4)

Gastrointestinal disorders

Not Known:

Chronic hepatic necrosis, liver damage, Acute pancreatitis, active hepatitis, constipation, GI irritation, biliary spasm, nausea, vomiting, loss of appetite, dry mouth, paralytic ileius or toxic megacolon.

Vascular disorders

Not Known:

Toxic myocarditis, bradycardia, palpitations, hypotension.

Blood and lymphatic system disorders

Not Known:

blood dyscrasias including methaemoglobinaemia, neutropenia, pancytopenia, leukopenia, thrombocytopenic purpura, haemolytic anaemia and agranulocytosis.

Renal and urinary disorders

Uncommon:

Nephrotoxicity, papillary necrosis

Not Known:

Ureteral spasm, antidiuretic effect.

Skin and subcutaneous tissue disorders

Rare:

Skin rash, drug fever, mucosal lesions.

Not Known:

Urticaria, difficulty breathing, increased sweating, redness or flushed face.

Eye disorders

Not Known:

blurred or double vision.

General disorders and administration site conditions

Uncommon:

Drug withdrawal syndrome

Other

Trembling, unusual tiredness or weakness, malaise, miosis, hypothermia.

Effects of withdrawal -abrupt withdrawal precipitates a withdrawal syndrome. Symptoms may include tremor, insomnia, nausea, vomiting, sweating and increase in heart rate, respiratory rate and blood pressure. NOTE tolerance diminishes rapidly after withdrawal so a previously tolerated dose may prove fatal.

Other effects -Most reports of adverse reactions to paracetamol relate to overdosage with the drug.

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 authorization 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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Paracetamol:

Symptoms: Pallor, nausea, vomiting, anorexia and abdominal pain in the first 24 hours. 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, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias 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.

Treatment: 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.

Opioids:

Symptoms: cold clammy skin, confusion, convulsions, severe drowsiness, tiredness, low blood pressure, pinpoint pupils of eyes, slow heart beat and respiratory rate coma.

Treatment: Treat respiratory depression or other life-threatening adverse effects first. Empty the stomach via gastric lavage or induction of emesis.

The opioid antagonist naloxone (0.42mg subcutaneous) can be given and repeated at 23 minute intervals to a maximum of 10mg. Naloxone may also be given by intramuscular injection or intravenous infusion. The patient should be monitored as the duration of opioid analgesic may exceed that of the antagonist.

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anilides, Paracetamol combinations excl. psycholeptics

ATC Code: N02B E51

Paracetamol has analgesic and antipyretic properties but is has no useful anti-inflammatory properties.

Codeine phosphate hemihydrate is a weak analgesic and is used in the treatment of cough and diarrhoea.

Paracetamol's effects are thought to be related to inhibition of prostaglandin synthesis.

Codeine is much less potent than morphine and it is inadequate against severe pain even in the largest tolerable doses. It does not cause appreciable respiratory depression but does have antitussive and constipating effects. It differs from morphine in that for normal medical use serious dependence is not frequently associated with codeine and large doses produce excitement rather than depression. 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. Codeine also binds weakly to κ opioid receptors which mediates spinal analgesia, sedation and miosis.

5.2 Pharmacokinetic properties

Codeine

Absorption and Distribution

Codeine and its salts are readily absorbed from the GI tract and ingestion of codeine phosphate produces peak plasma concentrations in about one hour.

Biotransformation and Excretion

It is metabolised in the liver; and codeine and its metabolites are entirely excreted almost by the kidney, mainly as conjugates with glucuronic acid. The plasma half-life is reported to be 3-4 hours after administration by mouth.

Paracetamol

Absorption and Distribution

Paracetamol is readily absorbed from the GI tract with peak plasma concentrations occurring about 30 minutes-2 hours after ingestion.

Biotransformation and Excretion

It is metabolised in the liver and excreted in the urine, mainly as the glucuronide and sulfate conjugates. The elimination half-life varies from about 1-4 hours.

Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations.

A minor hydroxylated metabolite which is usually produced in very small amounts by mixed-function oxidases in the liver and which is usually detoxified by conjugation with liver glutathione may accumulate following paracetamol overdosage and cause liver damage.

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 hydrogen carbonate

Sodium carbonate (anhydrous)

Sorbitol

Saccharin sodium

Citric Acid (anhydrous)

Polyethylene glycol 6000

Povidone K25

Simethicone

6.2 Incompatibilities

None stated.

6.3 Shelf life

Tube pack: Two years.

Strip pack: 12 months

6.4 Special precautions for storage

Do not store above 25°C.

Store your medicine in the original packaging in order to protect from moisture.

6.5 Nature and contents of container

Strip packs:

The Effervescent Tablets are available in Paper/PE/Aluminium/Surlyn Strip in following pack sizes.

Pack size: 10, 12, 16, 24, 30, 50, 56, 60, 100 or 112 tablets per carton.

Pack size(s) for strip: 4 or 10 tablets in a strip.

Polypropylene tube pack:

The Effervescent Tablets are packed in white opaque plain polypropylene tube and white opaque tamper evident polyethylene cap with inbuilt desiccant.

Pack size: 10 (1 x 10) tablets per carton, 16 (2 x 8) tablets per carton, 20 (1 x 20) tablets per carton, 24 (3 x 8) tablets per carton, 24 (1 x 24) tablets per carton, 30 (3 x 10) tablets per carton, 50 (5 x 10) tablets per carton, 56 (7 x 8) tablets per carton, 60 (3 x 20) tablets per carton, 100 (5 x 20) tablets per carton and 112 (14 x 8) tablets per carton.

Pack size(s) for tube pack: 8, 10, 20 or 24 tablets in a tube.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

ACCORD HEALTHCARE LIMITED

GROUND FLOOR, SAGE HOUSE

319 PINNER ROAD

HARROW

HA1 4HF

UNITED KINGDOM

8. Marketing authorisation number(s)

PL 20075/0516

9. Date of first authorisation/renewal of the authorisation

11/03/2009

10. Date of revision of the text

13/05/2020