This information is intended for use by health professionals

1. Name of the medicinal product

Co-codamol Effervescent Tablets 8/500mg

2. Qualitative and quantitative composition

Each tablet contains 8mg codeine phosphate hemihydrate and 500mg paracetamol.

For 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 treatment of pain, including muscular and rheumatic pains, headache, migraine, neuralgia, toothache, sore throat, period pains, aches and pains, discomfort associated with influenza, feverishness and feverish colds.

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

Prior to starting treatment with opioids, a discussion 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).

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

One to two tablets dissolved in water every 4 to 6 hours as required, to a maximum of 8 tablets in 24 hours.

Paediatric population:

Children 16-18 years:

One to two tablets every 6 hours when necessary to a maximum of 8 tablets in 24 hours

Children 12-15 years:

One tablet dissolved in water every 6 hours when necessary to a maximum of 4 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 sections 4.3 and 4.4).

Elderly

There is no current evidence for the alteration of the adult dose except where there is impaired hepatic function when dosage reduction may be necessary.

4.3 Contraindications

Conditions where morphine and opioids are contra-indicated e.g. acute alcoholism and where risk of paralytic ileus, acute respiratory depression, raised intracranial pressure or head injury (affects pupillary responses vital for neurological assessment).

• 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

• Sensitivity to codeine or paracetamol or any of the constituents of the tablets.

Co-codamol effervescent is not recommended for children under the age of 12 years.

4.4 Special warnings and precautions for use

Other paracetamol containing medication should be avoided when taking co-codamol effervescent tablets.

The tablets contain aspartame and so should not be taken by patients with phenylketonuria. This medicinal product contains 438mg sodium per tablet, equivalent to 22% of the WHO recommended maximum daily intake for sodium.

The maximum daily dose of this product is equivalent to 175% of the WHO recommended maximum daily intake for sodium.

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

Care should be taken when prescribing these tablets to patients with liver or renal impairment.

The hazards of paracetamol overdose are greater in those with non-cirrhotic alcoholic liver disease.

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:

Talk to your prescriber before taking this medicine if you:

• are or have ever been addicted to opioids, alcohol, prescription medicines, or illegal drugs.

• have previously suffered from withdrawal symptoms such as agitation, anxiety, shaking or sweating, when you have stopped taking alcohol or drugs.

• feel you need to take more of co-codamol to get the same level of pain relief, this may mean you are becoming tolerant to the effects of this medicine or are becoming addicted to it. Speak to your prescriber who will discuss your treatment and may change your dose or switch you to an alternative pain reliever.

Taking this medicine regularly, particularly for a long time, can lead to addiction. Your prescriber should have explained how long you will be taking it for and when it is appropriate to stop, how to do this safely.

Rarely, increasing the dose of this medicine can make you more sensitive to pain. If this happens, you need to speak to your prescriber about your treatment.

Addiction can cause withdrawal symptoms when you stop taking this medicine. Withdrawal symptoms can include restlessness, difficulty sleeping, irritability, agitation, anxiety, feeling your heartbeat (palpitations), increased blood pressure, feeling or being sick, diarrhoea, loss of appetite, shaking, shivering or sweating. Your prescriber will discuss with you how to gradually reduce your dose before stopping the medicine. It is important that you do not stop taking the medicine suddenly as you will be more likely to experience withdrawal symptoms.

Opioids should only be used by those they are prescribed for. Do not give your medicine to anyone else. Taking higher doses or more frequent doses of opioid, may increase the risk of addiction. Overuse and misuse can lead to overdose and/or death.

Codeine is transformed to morphine in the liver by an enzyme. Morphine is the substance that produces pain relief. Some people have a variation of this enzyme and this can affect people in different ways. In some people, morphine is not produced or produced in very small quantities, and it will not provide enough pain relief. Other people are more likely to get serious side effects because a very high amount of morphine is produced. If you notice any of the following side effects, you must stop taking this medicine and seek immediate medical advice: slow or shallow breathing, confusion, sleepiness, small pupils, feeling or being sick, constipation, lack of appetite.

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 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 ofmorphine 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.

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 hemihydrate 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

Avoid taking co-codamol effervescent tablets with CNS depressants or other paracetamol containing products. The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine. Opioid analgesics such as codeine antagonise the effects of domperidone or metoclopramide on gastrointestinal activity.

Co-administration with colestyramine may reduce absorption. Patients on anticoagulants may take occasional doses of co-codamol effervescent but the anticoagulant effect of warfarin and coumarins may be enhanced by regular administration of paracetamol.

Concurrent use with centrally acting muscle relaxants may increase the risk of respiratory depression.

Concurrent use of MAO inhibitors or tricyclic antidepressants with codeine may increase the effect of either the antidepressant or codeine. Concurrent use of anticholinergic and codeine may produce paralytic ileus.

MAOI's taken with pethidine have been associated with severe CNS excitation or depression (including hypertension or hypotension). Although this is 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.

Enzyme-inducing medicines, such as some antiepileptic drugs (phenytoin, phenobarbital, carbamazepine) have been shown in pharmacokinetic studies to reduce the plasma AUC of Paracetamol to approximately 60%. Other substances with enzyme inducing properties, e.g. rifampicin and St. John's wort (hypericum) are also suspected of causing lowered concentrations of Paracetamol. In addition, the risk of liver damage during treatment with maximum recommended doses of Paracetamol will be higher in patients being treated with enzyme-inducing agents.

4.6 Pregnancy and lactation

A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity.

Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency

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

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.

Breast feeding

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

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.

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 effervescent tablets.

4.8 Undesirable effects

Reported adverse reactions seem more prominent in ambulatory than non-ambulatory patients and some of these effects may be alleviated if the patient lies down.

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).

System Organ Class

Frequency

Adverse Effects

Blood and lymphatic system disorders

Not Known

Thrombocytopenia, agranulocytosis

Immune system disorders

Not Known

Anaphylactic reaction, hypersensitivity

Psychiatric disorders

Not known

Dysphoria, euphoria, confusion, Drug dependence

Nervous System disorders

Not known

Dizziness, sedation, headache, drowsiness

Ear and Labyrinth disorders

Not known

Deafness

Respiratory thoracic and mediastinal disorders

Not known

Bronchospasm, dyspnoea

Gastro-intestinal disorders

Not known

Nausea, vomiting, constipation, abdominal pain, pancreatitis.

Renal and urinary disorders

Not known

Urinary retention

Skin and subcutaneous tissue disorders

Not known

Pruritus, rash, urticarial, fixed drug eruption.

General disorders and administration site conditions

Uncommon

drug withdrawal syndrome

1 Deafness has been reported in patients after long term use of high doses of codeine – Paracetamol.

2 Drug-induced pancreatitis associated with Paracetamol has been reported in literature to be a rare reaction only occurring in patients taking in excess of the recommended doses. Literature reports have also associated cases of pancreatitis with codeine.

There have been cases of bronchospasm with Paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.

In clinical use of Paracetamol-containing products, there have been a few reports of blood dyscrasias including thrombocytopenia and agranulocytosis but these were not necessary causally related to Paracetamol.

Co-codamol effervescent tablets are generally well tolerated but hypersensitivity reactions including skin rashes may occur. Rare cases of anaphylaxis, angioedema, urticaria, pruritus and fixed drug eruption have been reported with medications containing paracetamol and/or codeine. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to Co-codamol.

Codeine may sometimes cause typical opioid effects such as vomiting, constipation, nausea, light-headedness, dizziness, confusion, drowsiness and urinary retention. The frequency and severity of these effects are determined by dosage, duration of treatment and individual sensitivity. There have been rare reports of acute pancreatitis in patients taking codeine or codeine/paracetamol combinations.

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 the yellow card scheme at www.mhra.gov.uk/yellowcard

4.9 Overdose

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.

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 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 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 maximumprotective 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 in 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

This 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

ATC Code: N02B E51

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

Paracetamol is rapidly and well absorbed from the intestinal tract after it has left the stomach. Plasma protein binding is low and paracetamol is metabolised in the liver and mainly excreted in the urine as glucuronide and sulphate conjugates. The elimination half-life is 1-3 hours.

Codeine is absorbed from the gastro-intestinal tract and peak plasma-codeine concentrations are found in about one hour. It is metabolised by O- and N- demethylation in the liver to morphine, norcodeine, and other metabolites including normorphine and hydrocodone. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid. The elimination half-life has been reported to be between 3 and 4 hours.

5.3 Preclinical safety data

Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.

6. Pharmaceutical particulars
6.1 List of excipients

Sodium hydrogen carbonate, citric acid, sodium carbonate, povidone, simeticone, sodium saccharin, aspartame (E951), 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 a dry place and protect from light.

6.5 Nature and contents of container

4 layer paper/PE/aluminium/PE blisters.

Pack sizes: 100 tablets.

6.6 Special precautions for disposal and other handling

None

7. Marketing authorisation holder

Kent Pharma UK Limited,

The Bower,

4 Roundwood Avenue,

Stockley Park,

Heathrow,

United Kingdom,

UB11 1AF

8. Marketing authorisation number(s)

PL 51463/0018

9. Date of first authorisation/renewal of the authorisation

27 April 2010

10. Date of revision of the text

29 May 2020